Tripartite androgen receptor eliminators, methods and uses thereof

ABSTRACT

The present specification discloses tripartite androgen receptor eliminators (AREs), pharmaceutical compositions and medicaments comprising such AREs, methods and uses for such AREs and compositions and medicaments, and methods and uses for AREs and compositions and medicaments for treating an androgen receptor signaling-mediated condition, disease or disorder.

This application is a national stage entry pursuant to 35 U.S.C. § 371of International Patent Application Serial No. PCT/US2018/030538, whichclaims the benefit of priority and the filing date pursuant to 35 U.S.C.§ 119(e) to U.S. Provisional Patent Application 62/492,822, filed May 1,2017, the content of each of which is hereby incorporated by referencein its entirety.

Androgens are well known to control the development and functions of thereproductive system in both male and female. The major circulatingandrogen is testosterone. Testosterone can be metabolized by5α-reductases into a more potent androgen, 5α-dihydrotestosterone (DHT).Both testosterone and DHT can bind to androgen receptors, but DHT hasten-fold higher affinity for androgen receptors compared totestosterone.

Dermatologists recognize many different types of skin-relatedconditions, diseases and disorders that affect the health of the skinand/or hair. The role of androgen receptor signaling has been implicatedin skin and hair physiology and pathogenesis based on the facts thatandrogen receptors and many androgenic steroidogenesis enzymes areexpressed in skin, and the presence of sexual dimorphism in the etiologyand diseases of skin and hair. While skin is not the major source ofandrogen synthesis, in sebocytes, sweat glands, and dermal papilla cellsof hair, circulating androgenic pro-hormones, dehydroepiandrosterone(DHEA) and androstenedione, can be converted into testosterone and DHT.These potent androgens subsequently regulate dermal physiology throughintracrine or paracrine manners. It has been shown that over-activationof androgen receptor by DHT has been shown to play a critical role inhair loss (alopecia) in males excess hair growth (hirsutism) in females.In addition, androgen receptor signaling is involved in excessive sebumproduction and appears to promote the abnormal or excessive inflammatoryresponses observed in many skin diseases, such as acne and psoriasis.

The present specification discloses new compounds, pharmaceuticalcompositions comprising these compounds and methods and uses oftargeting the androgen receptor using these compounds and compositionsin order to treat an androgen receptor signal mediated skin-relatedcondition, disease or disorder that affects the health of the skinand/or hair. Such treatments safely and effectively promote healthy skinand hair of an individual.

SUMMARY

Aspects of the present specification disclose a compound of formula IARA-L-EE  (I)wherein ARA is an androgen receptor (AR) antagonist, L is a linkermolecule and EE is an AR elimination promoter or elimination enhancerelement. An AR antagonist disclosed herein can be any molecule thatreduces or prevents agonist-mediated responses via an AR, including anorthosteric AR antagonist, an allosteric AR antagonist, or an ARantagonist that interacts at one or more unique binding sites notnormally involved in the biological regulation of AR activity. An ARantagonist disclosed herein may be reversible or irreversible. A linkerdisclosed herein can be of formula II

wherein R¹ and R² are each independently H, OH, COOH, NH₂, R³OH, R³COOH,OR³OH, OR³COOH, R³NH(CO)R⁴, R³NH(CO)R⁴OH, R³NH(CO)R⁴COOH; R³ and R⁴ areeach independently C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, or C₂₋₁₀ alkynyl; and nany integer from 0 to 10. An AR elimination promoter or eliminationenhancer element disclosed herein can be a hydrophobic tag or an E3ligase-recruiting moiety. A hydrophobic tag includes, withoutlimitation, an adamantane moiety or a Boc-protected amino acid. An E3ligase-recruiting moiety includes, without limitation, ahypoxia-inducible factor 1α (HIF-1α) moiety, a Nutlin moiety, a bestatinmoiety, or a phthalimide moiety.

Other aspects of the present specification disclose a pharmaceuticalcomposition comprising one or more compounds disclosed herein.

Other aspects of the present specification disclose a kit comprising oneor more compounds disclosed herein or one or more pharmaceuticalcomposition disclosed herein.

Other aspects of the present specification disclose a method of treatinghair loss in an individual comprising the step of administering atherapeutically effective amount of a compound disclosed herein or apharmaceutical composition disclosed herein. Aspects of the presentspecification also disclose a compound disclosed herein or apharmaceutical composition disclosed herein for use in the treatment ofhair loss; use of a compound disclosed herein or a pharmaceuticalcomposition disclosed herein for the treatment of hair loss; and use ofa compound disclosed herein or a pharmaceutical composition disclosedherein in the manufacture of a medicament for the treatment of hairloss.

Other aspects of the present specification disclose a method of treatinghair thinning in an individual comprising the step of administering atherapeutically effective amount of a compound disclosed herein or apharmaceutical composition disclosed herein. Aspects of the presentspecification also disclose a compound disclosed herein or a compounddisclosed herein or a pharmaceutical composition disclosed herein foruse in the treatment of hair thinning; use of a compound disclosedherein or a pharmaceutical composition disclosed herein for thetreatment of hair thinning; and use of a compound disclosed herein or apharmaceutical composition disclosed herein in the manufacture of amedicament for the treatment of hair thinning.

Other aspects of the present specification disclose a method of treatinghair color loss in an individual comprising the step of administering atherapeutically effective amount of a compound disclosed herein or apharmaceutical composition disclosed herein. Aspects of the presentspecification also disclose a compound disclosed herein or a compounddisclosed herein or a pharmaceutical composition disclosed herein foruse in the treatment of hair color loss; use of a compound disclosedherein or a pharmaceutical composition disclosed herein for thetreatment of hair color loss; and use of a compound disclosed herein ora pharmaceutical composition disclosed herein in the manufacture of amedicament for the treatment of hair color loss.

Other aspects of the present specification disclose a method of treatinga condition associated with a degenerative hair follicle disorder in anindividual comprising the step of administering a therapeuticallyeffective amount of a compound disclosed herein or a pharmaceuticalcomposition disclosed herein. Aspects of the present specification alsodisclose a compound disclosed herein or a compound disclosed herein or apharmaceutical composition disclosed herein for use in the treatment ofa condition associated with a degenerative hair follicle disorder; useof a compound disclosed herein or a pharmaceutical composition disclosedherein for the treatment of a condition associated with a degenerativehair follicle disorder; and use of a compound disclosed herein or apharmaceutical composition disclosed herein in the manufacture of amedicament for the treatment of a condition associated with adegenerative hair follicle disorder.

Other aspects of the present specification disclose a method ofimproving hair appearance in an individual comprising the step ofadministering a therapeutically effective amount of a compound disclosedherein or a pharmaceutical composition disclosed herein. Aspects of thepresent specification also disclose a compound disclosed herein or acompound disclosed herein or a pharmaceutical composition disclosedherein for use in improving hair appearance; use of a compound disclosedherein or a pharmaceutical composition disclosed herein for improvinghair appearance; and use of a compound disclosed herein or apharmaceutical composition disclosed herein in the manufacture of amedicament for improving hair appearance.

Other aspects of the present specification disclose a method of treatinga skin condition in an individual comprising the step of administering atherapeutically effective amount of a compound disclosed herein or apharmaceutical composition disclosed herein. Aspects of the presentspecification also disclose a compound disclosed herein or a compounddisclosed herein or a pharmaceutical composition disclosed herein foruse in the treatment of a skin condition; use of a compound disclosedherein or a pharmaceutical composition disclosed herein for thetreatment of a skin condition; and use of a compound disclosed herein ora pharmaceutical composition disclosed herein in the manufacture of amedicament for the treatment of a skin condition

DETAILED DESCRIPTION

The skin is the outer covering of a mammalian body and guards theunderlying muscles, bones, ligaments and internal organs. Typically thelargest organ of the integumentary system, skin is composed of threeprimary layers: the epidermis, the dermis and the hypodermis. Theepidermis is the outermost epithelial layer of the skin and forms thewaterproof, protective wrap over the body's surface which also serves asa barrier to infection. The dermis is an epithelial layer of skinbeneath the epidermis and serves to cushions the body from stress andstrain. The hypodermis lies below the dermis and comprises looseconnective tissue, adipose tissue and elastin. Although not composed ofepithelial tissue, and thus not part of the skin, the hypodermisattaches the skin to underlying bone and muscle as well as supplying itwith blood vessels and nerves.

Each hair comprises two structures: the hair shaft and the hairfollicle. The hair shaft is primary composed of keratin that isorganized into three layers called the medulla, cortex and cuticle. Themedulla is the inner layer is not necessarily present in all hair types.The next keratin layer is the cortex, the intermediate layer that makesup the majority of the hair shaft. The outer layer is the cuticle, whichis formed by tightly packed scales in an overlapping structure similarto roof shingles and is continuous with the root sheath. Most hairconditioning products attempt to affect the cuticle. Pigment cells, ormelanocytes, are distributed throughout the cortex and medulla givingthe hair its characteristic color. For purposes of the presentdisclosure, it is necessary to consider various types of hair,including, terminal hairs and vellus hairs and modified terminal hairs,such as seen in eye lashes and eyebrows. Terminal hairs are coarse,pigmented, long hairs in which the bulb of the hair follicle is seateddeep in the dermis. Vellus hairs, on the other hand, are fine, thin,non-pigmented short hairs in which the hair bulb is locatedsuperficially in the dermis. As alopecia progresses, a transition takesplace in the area of approaching baldness wherein the hairs themselvesare changing from the terminal to the vellus type.

Located in the dermal layer of the skin, the hair follicle can berecognized as a separate entity within the skin with formation andmaintenance based on interaction between dermal and epidermalcomponents. The follicle comprises several components. At the base ofthe follicle is a projection called a dermal papilla, which containscapillaries that supply nutrients to the portion of the follicle calledthe bulb. The bulb can be divided into two regions: a lower region ofundifferentiated cells, and an upper region of actively proliferatingcells, called matrix cells, that differentiated to form the inner sheathand the hair shaft. Matrix cells are actively proliferating cells whichdifferentiate and become keratinized to form the hair shaft. Duringepidermal cell differentiation (anagen phase), matrix cells divide every23 to 72 hours, faster than any other cells in the body. Matrix cellslocated in the immediate vicinity of the dermal papilla differentiateand become keratinized to form the hair shaft, whereas matrix cellstowards the periphery of a hair follicle proliferate and produce theinner root sheath. The follicle also contains two epidermal layerstermed the inner root sheath and outer root sheath. These sheathsprotect and mold the growing hair shaft. The inner root sheath can bedivided into three layers (cuticle, Huxley layer, and Henle layer) basedon structure, patterns of keratinization, and incorporation oftrichohyalin. The inner sheath follows the hair shaft until it ends justbelow the level of a sebaceous gland to leave only the hair shaft toprotrude above the epidermis. The outer root sheath continues all theway up to the gland and is distinct from other epidermal components ofthe hair follicle in that it is continuous with the epidermis. Thesebaceous gland produces sebum, a natural oil that conditions the hairshaft and sometimes an apocrine (scent) gland. An erector pili muscleattaches below the gland to a fibrous layer around the outer sheath. Thecontraction of the muscle pulls on both the hair to make it erect andpulls on the skin making a bumpy surface. Hair color is caused by apigment (melanin) that is produced by the hair follicle.

Under normal circumstances hair growth in each hair follicle occurs in acycle that can comprise at least four phases: anagen (growth phase),catagen (regression phase), telogen (resting phase), and exogen(shedding phase). The anagen phase is the active growth phase of thehair during which the matrix cells in the root of the hair are dividingrapidly. About 80-90% of all hairs are in this phase at any time. Anagenhairs are anchored deeply into the subcutaneous fat and cannot be pulledout easily. When a new hair is formed, it pushes the club hair up thefollicle and eventually out. During this phase the hair grows about 0.35mm a day (1 cm every 28 days), but this rate varies depending on thesite of the hair follicle and the age and sex of the individual. Humanscalp hair stays in the active anagen phase of growth for 2-6 years, ascompared to other sites like on the leg (which stays in the anagen phasefor 19 to 26 weeks), on the arm (from 6 to 12 weeks), and in themustache area, eyelashes, and eyebrows (from 4 to 14 weeks). Humansubjects that have difficulty growing their hair beyond a certain lengthhave a short active phase of growth. Human subjects that have very longhair have a long active phase of growth.

The catagen phase is a short transitional phase between the anagen andtelogen phases which lasts only about 7-21 days. Although brief, thisphase can be divided into eight subphases starting with late anagen andending in early telogen. About 1-3% of all hairs are in this phase atany time. It is a period of controlled regression in which the hairfollicle regresses and dismantles the hair growing part of the hairfollicle, in part, through apoptosis. During this phase there isinvolution of the hair follicle and a fundamental restructuring of theextracellular matrix by 1) a withdrawal of dermal papilla and stoppageof hair growth, 2) cessation of matrix cell proliferation and melanocytemelanin synthesis, 3) shrinkage of the outer root sheath and attachmentto the hair shaft, 4) movement of the lower hair follicle to the levelof the arrector pili muscle, 5) movement of the dermal papilla upwardthrough the skin, coming to rest beneath the hair-follicle bulge, and 6)cessation of protein and pigment production through programmed celldeath keratinocyte and melanocytes. Also, there is massive apotosis inthe bulbar, transient, portion of the hair follicle contributes toregression of the hair follicle and the formation of a fibrous streamerin the skin. The onset of these apoptotic events seems to bepredetermined and finely orchestrated, and as such the events in thisphase can be more appropriately described by the term, “programmed celldeath”.

The third phase is the telogen phase which, for all practical purposes,can be denominated a “resting phase.” About 10-15% of all hairs are inthis phase at any time. During this phase the hair follicle is stopsdividing and the hair shaft ceases to grow, the telogen hair completesdifferentiation, and the last hair growth cells cluster together at thebase of the hair shaft to form a club-structure comprising a centrallylying brush of keratinized cells surrounded by apparent mooring cellscontaining easily found, discrete nuclei and abundant cytoplasm. Calleda club hair, the cluster of cells actually holds the hair shaft in thetube of hair follicle. In the final aspect of the telogen phase, achemical signal causes matrix cells to initiate growth of a new hairshaft from the same hair follicle and the cycle starts over with a newanagen phase. Even though a telogen hair is located near the surface ofthe skin, it remains firmly anchored to the hair follicle. A telogenhair eventually sheds in the exogen phase and replaced by the nextbudding anagen hair. About 30-90 days elapse before telogen hair fromthe scalp sheds. The time period is much longer for hairs on theeyebrow, eyelash, arm and leg.

The final phase is the exogen, a phase marked by a highly controlled,active process where a telogen hair is actually shed from the follicle.The shed exogen hair has a shrunken base that is more elongated in shapeand has a scalloped and pitted margin. Within this shaft base there islittle associated cytoplasm and very few shrunken and fragmented nuclei.It is believed that the shrinkage of the hair club and disappears of thebrush mooring allows the exogen hair to be shed from the follicle.Normally about 25-150 exogen hairs are shed each day.

Recently, an addition phase called kenogen has been proposed. This phasedescribes the interval of the hair cycle in which the hair follicleremains empty after the telogen hair has been extruded, but before a newanagen hair reappears.

Androgens, mainly testosterone and 5α-dihydrotestosterone (DHT) playsignificant role in the growth and development of the male reproductiveorgans. These steroid hormones bring about their biological functionsthrough their associations with Androgen receptor (AR). Also known asnuclear receptor subfamily 3, group C, member 4 (NR3C4), AR is a 110 KDaligand dependent transcription factor that falls under the group ofnuclear receptor superfamily. AR has four functional domains, an Nterminal domain (NTD), a DNA binding domain (DBD), a hinge region and aLigand binding Domain (LBD). The DBD has ZNF motifs which allows it bindto DNA. The rest of the domains are involved in dimerization and ligandbinding. An AR is most closely related to the progesterone receptor, andprogestins in higher dosages can block AR. AR is found to be expressedin a number of tissues and cells including prostate, testis, seminalvesicle, epididymis, skin, skeletal muscle, cardiac muscle, liver andcentral nervous system. The main function of the AR receptor is as aDNA-binding transcription factor that regulates gene expression,including genes critical for the development and maintenance of the malesexual phenotype.

In the ligand unbound state, an AR is an inactive cytosolic protein,which is complex with various heat-shock proteins including Hsp70, Hsp90and Hsp 56 as well as p23. Upon ligand binding, two criticalphosphorylation events promote a conformational change to an AR,resulting in the release the LBD for hormone binding and disassociationof the ligand-bound AR from the Hsp complex. The complex-freeligand-bound AR translocates into the nucleus, forms homodimers, andbinds to the androgen-response elements (AREs) present on various targetgenes, thereby activating gene expression. Temporal and spatialexpression can be regulated in part by many co-regulators which bind toligand-bound AR homodimers at different time points and in differentcell types. For example, modulation of AR activity can be carried out byseveral transcription factors like ARA70, TR4, SRC family members andCBP/p300 and other associated proteins. FXXLF and WXXLF motifscontaining coactivators such as the p160 members bind with the AF2region of the LBD of an AR.

AR activity also drives hair loss, hair thinning, or hair color loss.For example, the dermal papilla is the master regulator of the haircycle and this structure has AR. DHT exposure to follicles on the vertexand frontal region of the scalp can suppress hair growth in part bydramatically shortening the length of anagen to point where the hairfollicle exists only in a miniaturized state of extended telogen. Inaddition, testosterone is converted to DHT in the follicle via theenzymatic activity of Type II 5-alpha reductase. Further, in androgenicalopecia is a common form of hair loss that begins to manifest itself inmales following the onset of puberty and increasing in frequency witheach decade of life. In the balding scalp of men levels of both AR andDHT are about 2-times higher than AR and DHT levels observed innon-balding scalp. Thus, although modulated by both genetic andenvironmental variables, the primary attribute of androgenic alopecia isincreased AR signaling resulting in the progressive shortening of thehair growth cycle in the hair follicle. It should be noted that femalealopecia also occurs and it thought to be regulated by factors similarto those involved with androgenic alopecia. Thus, targeting AR in amanner that reduces, suppresses or eliminates its signaling capabilitieswill prevent the progression of factors that drive hair loss, hairthinning, or hair color loss.

AR activity also drives certain skin conditions, disease and disorderssuch as, e.g., acne. Acne, also known as acne vulgaris, is a long-termskin disease that occurs when hair follicles are clogged with dead skincells and oil from the skin. It is characterized by blackheads orwhiteheads, pimples, greasy skin, and possible scarring. Acne primarilyaffects areas of the skin with a relatively high number of oil glands,including the face, upper part of the chest, and back. The resultingappearance can lead to anxiety, reduced self-esteem and, in extremecases, depression or thoughts of suicide. During puberty, an increase inandrogens in both males and females cause skin follicle glands to growlarger and produce more oily sebum. Acne has been linked to increasedexposure to testosterone, DHT, and dehydroepiandrosterone (DHEA), andsuch androgens appear to be essential for acne to occur, as acne doesnot develop in individuals with complete androgen insensitivity syndrome(CAIS). Thus, targeting AR in a manner that reduces, suppresses oreliminates its signaling capabilities will prevent the progression offactors that drive skin conditions, diseases and disorders such as acneor another AR signal-mediated skin condition, disease or disorder.

Besides being one of the most common skin disorders, acne is also acardinal component of many systemic diseases or syndromes. Theirassociation illustrates the nature of these diseases and is indicativeof the pathogenesis of acne. Congenital adrenal hyperplasia (CAH) andseborrhoea-acne-hirsutism-androgenetic alopecia (SAHA) syndromehighlight the role of androgen steroids, while polycystic ovary (PCO)and hyperandrogenism-insulin resistance-acanthosis nigricans (HAIR-AN)syndromes indicate insulin resistance in acne. Apert syndrome withincreased fibroblast growth factor receptor 2 (FGFR2) signalling resultsin follicular hyperkeratinization and sebaceous gland hypertrophy inacne. Synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) andpyogenic arthritis-pyoderma gangrenosum-acne (PAPA) syndromes highlightthe attributes of inflammation to acne formation.

The present specification discloses tripartite androgen receptoreliminators (AREs) which comprises an AR antagonist linked to a moleculethat marks the AR antagonist for proteasome degradation. Thus, thedisclosed AREs have the ability to both antagonize AR activity andtrigger the degradation of this receptor. The AREs disclosed hereineffectively penetrate the skin and/or scalp when topically applied totrigger cellular AR clearance, thereby resulting in the treatment ofskin and hair conditions, diseases and disorders mediated by ARsignaling, including, without limitation hair problems such asandrogenic alopecia and facial hirsuitism and/or skin problems such asacne, excessive sebum production, and post-wound scar formation.

Without wishing to be bound by any particular theory, it is thought thatthe disclosed AREs, compositions comprising one or more AREs, andmethods and uses of such compositions reduce or prevent a haircondition, disease or disorder mediated by AR signaling in order toreduce or prevent hair loss, hair thinning, and/or hair color lossmediated by AR signaling. This can be accomplished, without limitation,by reducing, suppressing or inhibiting AR signaling in a hair follicle,reducing or eliminating AR in the cytoplasm of a follicle follicleand/or dermal papilla, inducing a hair follicle into the anagen phaseand/or stimulating the matrix cells to form a new hair shaft, byprolonging the time period a hair follicle remains in anagen phasethereby enabling the follicle to produce a longer and/or thicker hairshaft, by increasing keratin deposition thereby producing a longerand/or thicker hair shaft, by increasing melanin deposition therebydarkening hair shaft color, by preventing or prolonging the catagenphase thereby increasing the time a hair remains in a follicle, byprolonging the time period a hair follicle remains in telogen phasethereby increasing the time a hair remains in a follicle, by preventingthe follicle to enter the exogen phase thereby stopping the release ofthe hair shaft, by stopping hair shaft release in the exogen phasethereby increasing the number of hairs and/or by stimulating new hairshaft growth thereby allowing the production of two or more hair shaftsper follicle, and/or by increasing the conversion of intermediate hairsinto terminal hairs. Therefore, at any given time during treatment,there are more hairs in follicles and decreased hair loss. The result isnot only an increase in length, thickness and/or darkness of hairs, butalso an increase in the number and/or density of hairs.

In addition, without wishing to be bound by any particular theory, it isthought that the disclosed AREs, compositions comprising one or moreAREs, and methods and uses of such compositions reduce or prevent a skincondition, disease or disorder mediated by AR signaling. This can beaccomplished, without limitation, by reducing, suppressing or inhibitingAR signaling in a skin follicle, and reducing or eliminating AR in thecytoplasm of a cell. Therefore, at any given time during treatment, thesymptoms or unwanted attributes of a skin condition, disease or disorderare reduced, suppressed or eliminated.

The present specification discloses, in part, a tripartite androgenreceptor eliminator (ARE). AN ARE comprises an AR antagonist, a linkermolecule and an AR elimination promoter or elimination enhancer element.In one embodiment, an ARE is of formula I:ARA-L-EE  (I)wherein ARA is an AR antagonist, L is a linker molecule and EE is an ARelimination promoter or elimination enhancer element.

The present specification discloses, in part, an AR receptor antagonist.An AR antagonist, also called an AR blocker, reduces or preventsagonist-mediated responses mediated by an AR, rather than provoking abiological response itself upon binding to an AR. Thus, an AR antagonisthas affinity but no efficacy for its cognate AR, and binding willdisrupt the interaction and inhibit the function of an AR agonist or aninverse AR agonist at an AR. An AR antagonist disclosed herein canmediate its effects by binding to an active orthosteric site or bybinding to an allosteric site on an AR, or an AR antagonist disclosedherein may interact at unique binding sites not normally involved in thebiological regulation of AR activity. An AR antagonist disclosed hereinmay be reversible or irreversible depending on the longevity of theantagonist-receptor complex, which, in turn, depends on the nature ofantagonist-receptor binding. Without wishing to be limited to any onetheory, AR degradation in cells can be triggered by disrupting theHSP90/AR complex in the cytoplasm, thereby causing AR clearance via theproteasome.

In one embodiment, an AR antagonist disclosed herein is flutamide,nilutamide, bicalutamide, enzalutamide, apalutamide, cyproteroneacetate, megestrol acetate, chlormadinone acetate, spironolactone,canrenone, drospirenone, ketoconazole, topilutamide (fluridil), orcimetidine. In an aspect of this embodiment, an AR antagonist disclosedherein is spironolactone, ketoconazole, methoxybenzyl lactam, RU58841 orCompound ARA1.

Other antagonists useful as an AR antagonist disclosed herein aredescribed in, e.g., U.S. Pat. Nos. 6,790,979; 8,198,323; Hu, et al.,Synthesis and Biological Evaluation of Amino-Pyridines as AndrogenReceptor Antagonists for Stimulating Hair Growth and Reducing SebumProduction, Bioorg. Med. Chem. Lett. 17: 5693-5697 (2007); Hu, et al.,(1R,2S)-4-(2-Cyano-cydohexyl-oxy)-2-trifluoromethy 1-benzonitrile, aPotent Androgen Receptor Antagonists for Stimulating Hair Growth andReducing Sebum Production, Bioorg. Med. Chem. Lett. 17: 5983-5988(2007); Mitchell, et al., Rational Design of a Topical Androgen ReceptorAntagonist for the Suppression of Sebum. Production with PropertiesSuitable for Follicular Delivery, J. Med. Chem. 53: 4422-4427 (2010),each of which is incorporated by reference in its entirety.

The present specification discloses, in part, a linker. A linkerdisclosed herein is a molecule that directly or indirectly attaches anandrogen receptor antagonist to an AR elimination promoter orelimination enhancer element. Typically, this attachment is a covalentattachment.

In one embodiment, a linker molecule is of formula II:

wherein R¹ and R² are each independently H, OH, COOH, NH₂, R³OH, R³COOH,OR³OH, OR³COOH, R³NH(CO)R⁴, R³NH(CO)R⁴OH, R³NH(CO)R⁴COOH; R³ and R⁴ areeach independently C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, or C₂₋₁₀ alkynyl; and nany integer from 0 to 10. An alkyl functional group comprising astraight-chain or branched-chain hydrocarbon linked exclusively bysingle bonds and not having any cyclic structure. An alkenyl functionalgroup comprising a straight-chain or branched-chain hydrocarbon havingone or more carbon-carbon double bonds and not having any cyclicstructure. An alkynyl functional group comprising a straight-chain orbranched-chain hydrocarbon having one or more carbon-carbon triple bondsand not having any cyclic structure.

In aspects of this embodiment, a linker molecule disclosed herein is offormula II, wherein R¹ and R² are each independently H, OH, COOH, NH₂,R³OH, R³COOH, OR³OH, OR³COOH, R³NH(CO)R⁴, R³NH(CO)R⁴OH, orR³NH(CO)R⁴COOH; R³ and R⁴ are each independently C₁₋₆ alkyl, C₂₋₆alkenyl, or C₂₋₆ alkynyl; and n any integer from 0 to 10. In otheraspects of this embodiment, a linker molecule disclosed herein is offormula II, wherein R¹ and R² are each independently H, OH, COOH, NH₂,R³OH, R³COOH, OR³OH, OR³COOH, R³NH(CO)R⁴, R³NH(CO)R⁴OH, orR³NH(CO)R⁴COOH; R³ and R⁴ are each independently C₁₋₄ alkyl, C₂₋₄alkenyl, or C₂₋₄ alkynyl; and n any integer from 0 to 5. In yet aspectsof this embodiment, a linker molecule disclosed herein is of formula II,wherein R¹ and R² are each independently H, OH, COOH, NH₂, R³OH, R³COOH,OR³OH, OR³COOH, or R³NH(CO)R⁴OH; R³ and R⁴ are each independently C₁₋₁₀alkyl; and n any integer from 0 to 10. In still other aspects of thisembodiment, a linker molecule disclosed herein is of formula II, whereinR¹ and R² are each independently H, OH, COOH, NH₂, R³OH, R³COOH, OR³OH,OR³COOH, or R³NH(CO)R⁴OH; R³ and R⁴ are each independently C₁₋₆ alkyl;and n any integer from 0 to 10. In other aspects of this embodiment, alinker molecule disclosed herein is of formula II, wherein R¹ and R² areeach independently H, OH, COOH, NH₂, R³OH, R³COOH, OR³OH, OR³COOH, orR³NH(CO)R⁴OH; R³ and R⁴ are each independently C₁₋₆ alkyl; and n anyinteger from 0 to 5.

In aspects of this embodiment, a linker molecule disclosed herein is offormula II, wherein R¹ is OH, COOH, NH₂, R³OH, R³COOH, or R³NH(CO)R⁴OH;R² is OH, COOH, NH₂, R³COOH, or OR³COOH, R³ and R⁴ are eachindependently C₁₋₁₀ alkyl; and n any integer from 0 to 10. In otheraspects of this embodiment, a linker molecule disclosed herein is offormula II, wherein R¹ is OH, COOH, NH₂, R³OH, R³COOH, or R³NH(CO)R⁴OH;R² is OH, COOH, NH₂, R³COOH, or OR³COOH, R³ and R⁴ are eachindependently C₁₋₆ alkyl; and n any integer from 0 to 10. In yet otheraspects of this embodiment, a linker molecule disclosed herein is offormula II, wherein R¹ is OH, COOH, NH₂, R³OH, R³COOH, or R³NH(CO)R⁴OH;R² is OH, COOH, NH₂, R³COOH, or OR³COOH, R³ and R⁴ are eachindependently C₁₋₆ alkyl; and n any integer from 0 to 5. In still otheraspects of this embodiment, a linker molecule disclosed herein is offormula II, wherein R¹ is OH, R³OH, R³COOH, or R³NH(CO)R⁴OH; R² is OH,COOH, NH₂, R³COOH, or OR³COOH, R³ and R⁴ are each independently C₁₋₆alkyl; and n any integer from 0 to 5. In other aspects of thisembodiment, a linker molecule disclosed herein is of formula II, whereinR¹ is OH, R³OH, R³COOH, or R³NH(CO)R⁴OH; R² is OH, COOH, NH₂, R³COOH, orOR³COOH, R³ and R⁴ are each independently C₁₋₄ alkyl; and n any integerfrom 0 to 4.

In aspects of this embodiment, a linker molecule disclosed herein is offormula II, wherein R¹ is OH, C—C—OH, C—COOH, or C—C—NH—CO—C—C—C—OH; R²is OH, COOH, NH₂, C—COOH, or O—C—COOH; and n any integer from 0 to 10.In other aspects of this embodiment, a linker molecule disclosed hereinis of formula II, wherein R¹ is OH, C—C—OH, C—COOH, orC—C—NH—CO—C—C—C—OH; R² is OH, COOH, NH₂, C—COOH, or O—C—COOH; and n anyinteger from 0 to 8. In yet other aspects of this embodiment, a linkermolecule disclosed herein is of formula II, wherein R¹ is OH, C—C—OH,C—COOH, or C—C—NH—CO—C—C—C—OH; R² is OH, COOH, NH₂, C—COOH, or O—C—COOH;and n any integer from 0 to 6. In still other aspects of thisembodiment, a linker molecule disclosed herein is of formula II, whereinR¹ is OH, C—C—OH, C—COOH, or C—C—NH—CO—C—C—C—OH; R² is OH, COOH, NH₂,C—COOH, or O—C—COOH; and n any integer from 0 to 4.

In other aspects of this embodiment, a linker molecule disclosed hereinis of formula III:

wherein n any integer from 0 to 10. In aspects of this embodiment, alinker molecule disclosed herein is of formula III, wherein n anyinteger from 0 to 8. In yet other aspects of this embodiment, a linkermolecule disclosed herein is of formula III, wherein n any integer from0 to 6. In still other aspects of this embodiment, a linker moleculedisclosed herein is of formula III, wherein n any integer from 0 to 4.In other aspects of this embodiment, a linker molecule disclosed hereinof formula III is

In other aspects of this embodiment, a linker molecule disclosed hereinis of formula IV:

wherein n any integer from 0 to 10. In aspects of this embodiment, alinker molecule disclosed herein is of formula IV, wherein n any integerfrom 0 to 8. In yet other aspects of this embodiment, a linker moleculedisclosed herein is of formula IV, wherein n any integer from 0 to 6. Instill other aspects of this embodiment, a linker molecule disclosedherein is of formula IV, wherein n any integer from 0 to 4. In otheraspects of this embodiment, a linker molecule disclosed herein offormula IV is

In other aspects of this embodiment, a linker molecule disclosed hereinis of formula V:

wherein n any integer from 0 to 10. In aspects of this embodiment, alinker molecule disclosed herein is of formula V, wherein n any integerfrom 0 to 8. In yet other aspects of this embodiment, a linker moleculedisclosed herein is of formula V, wherein n any integer from 0 to 6. Instill other aspects of this embodiment, a linker molecule disclosedherein is of formula V, wherein n any integer from 0 to 4. In otheraspects of this embodiment, a linker molecule disclosed herein offormula V is

In other aspects of this embodiment, a linker molecule disclosed hereinis of formula VI:

wherein n any integer from 0 to 10. In aspects of this embodiment, alinker molecule disclosed herein is of formula VI, wherein n any integerfrom 0 to 8. In yet other aspects of this embodiment, a linker moleculedisclosed herein is of formula VI, wherein n any integer from 0 to 6. Instill other aspects of this embodiment, a linker molecule disclosedherein is of formula VI, wherein n any integer from 0 to 4. In otheraspects of this embodiment, a linker molecule disclosed herein offormula VI is

In other aspects of this embodiment, a linker molecule disclosed hereinis of formula VII:

wherein n any integer from 0 to 10. In aspects of this embodiment, alinker molecule disclosed herein is of formula VII, wherein n anyinteger from 0 to 8. In yet other aspects of this embodiment, a linkermolecule disclosed herein is of formula VII, wherein n any integer from0 to 6. In still other aspects of this embodiment, a linker moleculedisclosed herein is of formula VII, wherein n any integer from 0 to 4.In other aspects of this embodiment, a linker molecule disclosed hereinof formula VII is

In other aspects of this embodiment, a linker molecule disclosed hereinis of formula VIII:

wherein n any integer from 0 to 10. In aspects of this embodiment, alinker molecule disclosed herein is of formula VIII, wherein n anyinteger from 0 to 8. In yet other aspects of this embodiment, a linkermolecule disclosed herein is of formula VIII, wherein n any integer from0 to 6. In still other aspects of this embodiment, a linker moleculedisclosed herein is of formula VIII, wherein n any integer from 0 to 4.In other aspects of this embodiment, a linker molecule disclosed hereinof formula VIII is

In other aspects of this embodiment, a linker molecule disclosed hereinis of formula IX:

wherein n any integer from 0 to 10. In aspects of this embodiment, alinker molecule disclosed herein is of formula IX, wherein n any integerfrom 0 to 8. In yet other aspects of this embodiment, a linker moleculedisclosed herein is of formula IX, wherein n any integer from 0 to 6. Instill other aspects of this embodiment, a linker molecule disclosedherein is of formula IX, wherein n any integer from 0 to 4. In otheraspects of this embodiment, a linker molecule disclosed herein offormula IX is

In other aspects of this embodiment, a linker molecule disclosed hereinis of formula X:

wherein n any integer from 0 to 10. In aspects of this embodiment, alinker molecule disclosed herein is of formula X, wherein n any integerfrom 0 to 8. In yet other aspects of this embodiment, a linker moleculedisclosed herein is of formula X, wherein n any integer from 0 to 6. Instill other aspects of this embodiment, a linker molecule disclosedherein is of formula X, wherein n any integer from 0 to 4. In otheraspects of this embodiment, a linker molecule disclosed herein offormula X is

The present specification discloses, in part, an AR elimination promoteror elimination enhancer element. An AR elimination promoter orelimination enhancer element disclosed herein targets, induces,facilitates or otherwise marks a polypeptide linked to the ARelimination promoter or elimination enhancer element as a polypeptidethat should be degraded, destroyed or otherwise made inactive ornon-functional. In one embodiment, an AR elimination promoter orelimination enhancer element disclosed herein targets, facilitates orotherwise marks a polypeptide for the proteasomal degradation pathway.In an aspect of this embodiment, an AR elimination promoter orelimination enhancer element disclosed herein targets, facilitates orotherwise marks a polypeptide for degradation by a proteasome using anubiquitin-independent pathway. In another aspect of this embodiment, anAR elimination promoter or elimination enhancer element disclosed hereintargets, facilitates or otherwise marks a polypeptide for degradation bya proteasome using an ubiquitin-dependent pathway.

In one embodiment, an AR elimination promoter or elimination enhancerelement is a hydrophobic tag. A hydrophobic tag is a molecule thatappears to destabilize a polypeptide, thereby resulting in therecruitment of one or more chaperones to an unfolded polypeptide. Thedestabilized protein is then transported to proteasomes where it isdegraded. Degradation using a hydrophobic tag appears to be anubiquitin-independent process. Examples of a hydrophobic tag is anadamantane moiety and a butyl carbamate (Boc)-protected amino acid.

In one aspect of this embodiment, a hydrophobic tag is an adamantanemoiety. An adamantine moiety disclosed herein comprises a C₁₀H₁₆cycloalkane arranged in an “armchair” configuration of four connectedcyclohexane rings. A boat-shaped configuration can also exist. Inaspects of this embodiment, an adamantine is of formula XI:

wherein R⁵ is H, OH, COOH, NH₂, a halogen, R⁶OH, R⁶COOH, R⁶C(O)NH₂, orR⁶C(O)R⁷; R⁶ is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, or C₂₋₁₀ alkynyl; and R⁷ isa halogen. A halogen refers to a nonmetal element including fluorine(F), chlorine (Cl), bromine (Br), iodine (I), astatine (At) andununseptium (Uus). In aspects of this embodiment, an adamantine moietydisclosed herein is of formula XI, wherein R⁵ is H, OH, COOH, NH₂, ahalogen, R⁶OH, R⁶COOH, R⁶C(O)NH₂ or R⁶C(O)R⁷; R⁶ is C₁₋₆ alkyl, C₂₋₆alkenyl, or C₂₋₆ alkynyl; and R⁷ is a halogen. In other aspects of thisembodiment, an adamantine moiety disclosed herein is of formula XI,wherein R⁵ is H, OH, COOH, NH₂, a halogen, R⁶OH, R⁶COOH, R⁶C(O)NH₂ orR⁶C(O)R⁷; R⁶ is C₁₋₄ alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl; and R⁷ is ahalogen. In yet other aspects of this embodiment, an adamantine moietydisclosed herein is of formula XI, wherein R⁵ is H, OH, COOH, NH₂, F,Br, Cl, I, R⁶OH, R⁶COOH, R⁶C(O)NH₂ or R⁶C(O)R⁷; R⁶ is C₁₋₆ alkyl, C₂₋₆alkenyl, or C₂₋₆ alkynyl; and R⁷ is a F, Br, Cl or I. In still otheraspects of this embodiment, an adamantine moiety disclosed herein offormula XI is

In another aspect of this embodiment, a hydrophobic tag is aBoc-protected amino acid. A Boc-protected amino acid induces proteindegradation by taking advantage of the N-end rule pathway, where thehalf-life of a polypeptide is determined by the specific N-terminalamino acid present. The following amino acids all confer half-life ofless than 90 minutes to a polypeptide: glutamine, arginine, glutamicacid, phenylalanine, aspartic acid, cysteine, lysine and aspartame. Inaspects of this embodiment, a hydrophobic tag is a tert-butylcarbamate-protected arginine (BOC₃Arg) moiety, an iso-butylcarbamate-protected lysine (BOC₂Lys) moiety, an iso-butylcarbamate-protected aspartic acid (BOC₂Asp) moiety, an iso-butylcarbamate-protected asparagine (BOC₂Asn) moiety, an iso-butylcarbamate-protected glutamic acid (BOC₂Glu) moiety, and an iso-butylcarbamate-protected glutamine (BOC₂Gln) moiety. In aspects of thisembodiment, a hydrophobic tag is

Additional hydrophobic tags useful as an AR elimination promoter orelimination enhancer element disclosed herein are described in, e.g.,Neklesa, et al., Small-Molecule Hydrophobic Tagging Induced Degradationof HaloTag Fusion Proteins, Nat. Chem. Biol. 7(8): 538-543 (2012), whichis hereby incorporated by reference in its entirety.

In one embodiment, an AR elimination promoter or elimination enhancerelement is an E3 ligase-recruiting moiety. An E3 ligase-recruitingmoiety recruits an ubiquitin E3 ligase to ubiquitylate a polypeptide ofinterest, thereby making the entire complex for degradation via theubiquitination pathway. Degradation using an E3 ligase-recruiting moietyis an ubiquitin-dependent process.

In one aspect of this embodiment, an E3 ligase-recruiting moiety is ahypoxia-inducible factor 1α (HIF-1α). A HIF-1α moiety recognizes a corehydroxylated proline in a seven-amino-acid recognition sequence ofhypoxia-inducible factor 1α (HIF-1α). In an aspect of this embodiment, aHIF-1α moiety is formula XII

wherein R⁸ is H, OH, COOH, NH₂, a halogen, R⁹OH, R⁹COOH, R⁹C(O)NH₂, orR⁹C(O)R¹⁰; R⁹ is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, or C₂₋₁₀ alkynyl; and R¹⁰is a halogen. In aspects of this embodiment, a HIF-1α moiety disclosedherein is of formula XII, wherein R⁸ is H, OH, COOH, NH₂, a halogen,R⁹OH, R⁹COOH, R⁹C(O)NH₂, or R⁹C(O)R¹⁰; R⁹ is C₁₋₆ alkyl, C₂₋₆ alkenyl,or C₂₋₆ alkynyl; and R¹⁰ is a halogen. In other aspects of thisembodiment, a HIF-1α moiety disclosed herein is of formula XII, whereinR⁸ is H, OH, COOH, NH₂, a halogen, R⁹OH, R⁹COOH, R⁹C(O)NH₂, orR⁹C(O)R¹⁰; R⁹ is C₁₋₄ alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl; and R¹⁰ is ahalogen. In yet other aspects of this embodiment, a HIF-1α moietydisclosed herein is of formula XII, wherein R⁸ is H, OH, COOH, NH₂, F,Br, Cl, I, R⁹OH, R⁹COOH, R⁹C(O)NH₂, or R⁹C(O)R¹⁰; R⁹ is C₁₋₆ alkyl, C₂₋₆alkenyl, or C₂₋₆ alkynyl; and R¹⁰ is a F, Br, Cl or I. In still otheraspects of this embodiment, a HIF-1α moiety disclosed herein of formulaXII is

In another aspect of this embodiment, an E3 ligase-recruiting moiety isa Nutlin moiety. A Nutlin moiety is a cis-imidazoline analog thatinhibit the interaction between mouse double minute 2 (MDM2) and tumorsuppressor p53. A Nutlin moiety includes a Nutlin-1 moiety, a Nutlin-2moiety and a Nutlin-3 moiety. In an aspect of this embodiment, a Nutlinmoiety is formula XIII

wherein R¹¹ is H, OH, COOH, NH₂, a halogen, R¹²OH, R¹²COOH, R¹²C(O)NH₂,or R¹²C(O)R¹³; R¹² is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, or C₂₋₁₀ alkynyl; andR¹³ is a halogen. In aspects of this embodiment, a Nutlin moietydisclosed herein is of formula XIII, wherein R¹¹ is H, OH, COOH, NH₂, ahalogen, R¹²OH, R¹²COOH, R¹²C(O)NH₂, or R¹²C(O)R¹³; R¹² is C₁₋₆ alkyl,C₂₋₆ alkenyl, or C₂₋₆ alkynyl; and R¹³ is a halogen. In other aspects ofthis embodiment, a Nutlin moiety disclosed herein is of formula XIII,wherein R¹¹ is H, OH, COOH, NH₂, a halogen, R¹²OH, R¹²COOH, R¹²C(O)NH₂,or R¹²C(O)R¹³; R¹² is C₁₋₄ alkyl, C₂₋₄alkenyl, or C₂₋₄ alkynyl; and R¹³is a halogen. In yet other aspects of this embodiment, a Nutlin moietydisclosed herein is of formula XIII, wherein R¹¹ is H, OH, COOH, NH₂, F,Br, Cl, I, R¹²OH, R¹²COOH, R¹²C(O)NH₂, or R¹²C(O)R¹³; R¹² is C₁₋₆ alkyl,C₂₋₆ alkenyl, or C₂₋₆ alkynyl; and R¹³ is a F, Br, Cl or I.

In another aspect of this embodiment, an E3 ligase-recruiting moiety isa bestatin moiety. A bestatin (also known as ubenimex) moiety is acompetitive, reversible protease inhibitor. In an aspect of thisembodiment, a bestatin moiety is formula XIV

wherein R¹⁴ is H, OH, COOH, NH₂, a halogen, R¹⁵OH, R¹⁵COOH, R¹⁵C(O)NH₂,or R¹⁵C(O)R¹⁶; R¹⁵ is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, or C₂₋₁₀ alkynyl; andR¹⁶ is a halogen. In aspects of this embodiment, a bestatin moietydisclosed herein is of formula XIV, wherein R¹⁴ is H, OH, COOH, NH₂, ahalogen, R¹⁵OH, R¹⁵COOH, R¹⁵C(O)NH₂, or R¹⁵C(O)R¹⁶; R¹⁵ is C₁₋₆ alkyl,C₂₋₆ alkenyl, or C₂₋₆ alkynyl; and R¹⁶ is a halogen. In other aspects ofthis embodiment, a bestatin moiety disclosed herein is of formula XIV,wherein R¹⁴ is H, OH, COOH, NH₂, a halogen, R¹⁵OH, R¹⁵COOH, R¹⁵C(O)NH₂,or R¹⁵C(O)R¹⁶; R¹⁵ is C₁₋₄ alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl; and R¹⁶is a halogen. In yet other aspects of this embodiment, a bestatin moietydisclosed herein is of formula XIV, wherein R¹⁴ is H, OH, COOH, NH₂, F,Br, Cl, I, R¹⁵OH, R¹⁵COOH, R¹⁵C(O)NH₂, or R¹⁵C(O)R¹⁶; R¹⁵ is C₁₋₆ alkyl,C₂₋₆ alkenyl, or C₂₋₆ alkynyl; and R¹⁶ is a F, Br, Cl or I.

In another aspect of this embodiment, an E3 ligase-recruiting moiety isa phthalimide moiety. A phthalimide moiety is a competitive, reversibleprotease inhibitor. A phthalimide moiety is a molecule comprising aphthalimide, C₆H₄(CO)₂NH. A phthalimide moiety includes thalidomide,lenalidomide and pomalidomide. In an aspect of this embodiment, aphthalimide moiety is formula XV

wherein R¹⁷ is H, OH, COOH, NH₂, a halogen, R¹⁹OH, R¹⁹COOH, R¹⁹C(O)NH₂,or R¹⁹C(O)R²⁰, NHR¹⁹OH, NHR¹⁹COOH, NHR¹⁹C(O)NH₂, or NHR¹⁹C(O)R²⁰; R¹⁸ isH, OH, O, COOH, or C₁₋₆; R¹⁹ is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, or C₂₋₁₀alkynyl; and R²⁰ is a halogen. In aspects of this embodiment, aphthalimide moiety disclosed herein is of formula XV, wherein R¹⁷ is H,OH, COOH, NH₂, a halogen, R¹⁹OH, R¹⁹COOH, R¹⁹C(O)NH₂, or R¹⁹C(O)R²⁰,NHR¹⁹OH, NHR¹⁹COOH, NHR¹⁹C(O)NH₂, or NHR¹⁹C(O)R²⁰; R¹⁸ is H, OH, O,COOH, or C₁₋₆; R¹⁹ is C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; and R²⁰is a halogen. In other aspects of this embodiment, a phthalimide moietydisclosed herein is of formula XV, wherein R¹⁷ is H, OH, COOH, NH₂, ahalogen, R¹⁹OH, R¹⁹COOH, R¹⁹C(O)NH₂, or R¹⁹C(O)R²⁰, NHR¹⁹OH, NHR¹⁹COOH,NHR¹⁹C(O)NH₂, or NHR¹⁹C(O)R²⁰; R¹⁸ is H, OH, O, COOH, or C₁₋₆; R¹⁹ isC₁₋₄ alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl; and R²⁰ is a halogen. In yetother aspects of this embodiment, a phthalimide moiety disclosed hereinis of formula XV, wherein R¹⁷ is H, OH, COOH, NH₂, F, Br, Cl, I, R¹⁹OH,R¹⁹COOH, R¹⁹C(O)NH₂, or R¹⁹C(O)R²⁰, NHR¹⁹OH, NHR¹⁹COOH, NHR¹⁹C(O)NH₂, orNHR¹⁹C(O)R²⁰; is H, OH, O, COOH, or C₁₋₆; R¹⁹ is C₁₋₆ alkyl, C₂₋₆alkenyl, or C₂₋₆ alkynyl; and R²⁰ is a F, Br, Cl or I.

In another aspect of this embodiment, a phthalimide moiety is any one offormulas XVI, XVII, XVIII or XIX

wherein R²⁰ is H, OH, COOH, NH₂, a halogen, R²¹OH, R²¹COOH, R²¹C(O)NH₂,or R²¹C(O)R²²; R²¹ is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, or C₂₋₁₀ alkynyl; andR²² is a halogen. In aspects of this embodiment, a phthalimide moietydisclosed herein is any one of formulas XVI, XVII, XVIII or XIX, whereinR²⁰ is H, OH, COOH, NH₂, a halogen, R²¹OH, R²¹COOH, R²¹C(O)NH₂, orR²¹C(O)R²²; R²¹ is C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; and R²² isa halogen. In other aspects of this embodiment, a phthalimide moietydisclosed herein is any one of formulas XVI, XVII, XVIII or XIX, whereinR²⁰ is H, OH, COOH, NH₂, a halogen, R²¹OH, R²¹COOH, R²¹C(O)NH₂, orR²¹C(O)R²²; and R²¹ is C₁₋₄ alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl; andR²² is a halogen. In yet other aspects of this embodiment, a phthalimidemoiety disclosed herein is any one of formulas XVI, XVII, XVIII or XIX,wherein R²⁰ is H, OH, COOH, NH₂, F, Br, Cl, I, R²¹OH, R²¹COOH,R²¹C(O)NH₂, or R²¹C(O)R²²; and R²¹ is C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆alkynyl; and R²² is a F, Br, Cl or I.

In an embodiment, an ARE disclosed herein is of formula XX:

wherein n any integer from 0 to 10. In aspects of this embodiment, anARE disclosed herein is of formula X, wherein n any integer from 0 to 8.In yet other aspects of this embodiment, an ARE disclosed herein is offormula XX, wherein n any integer from 0 to 6. In still other aspects ofthis embodiment, an ARE disclosed herein is of formula XX, wherein n anyinteger from 0 to 4. In other aspects of this embodiment, an AREdisclosed herein is

In an embodiment, an ARE disclosed herein is:

In an embodiment, an ARE disclosed herein is of formula XXI:

wherein n any integer from 0 to 10. In aspects of this embodiment, anARE disclosed herein is of formula XXI, wherein n any integer from 0 to8. In yet other aspects of this embodiment, an ARE disclosed herein isof formula XXI, wherein n any integer from 0 to 6. In still otheraspects of this embodiment, an ARE disclosed herein is of formula XXI,wherein n any integer from 0 to 4. In other aspects of this embodiment,an ARE disclosed herein is

In an embodiment, an ARE disclosed herein is:

In an embodiment, an ARE disclosed herein is of formula XXII:

wherein n any integer from 0 to 10. In aspects of this embodiment, anARE disclosed herein is of formula XXII, wherein n any integer from 0 to8. In yet other aspects of this embodiment, an ARE disclosed herein isof formula XXII, wherein n any integer from 0 to 6. In still otheraspects of this embodiment, an ARE disclosed herein is of formula XXII,wherein n any integer from 0 to 4. In other aspects of this embodiment,an ARE disclosed herein is

In an embodiment, an ARE disclosed herein is of formula XXIII:

wherein n any integer from 0 to 10. In aspects of this embodiment, anARE disclosed herein is of formula XXIII, wherein n any integer from 0to 8. In yet other aspects of this embodiment, an ARE disclosed hereinis of formula XXIII, wherein n any integer from 0 to 6. In still otheraspects of this embodiment, an ARE disclosed herein is of formula XXIII,wherein n any integer from 0 to 4. In other aspects of this embodiment,an ARE disclosed herein is

Aspects of the present specification disclose, in part, a pharmaceuticalcomposition. A pharmaceutical composition refers to a therapeuticallyeffective concentration of an active ingredient, such as, e.g., any ofthe AREs disclosed herein. Preferably, the pharmaceutical compositiondoes not produce an adverse, allergic, or other untoward or unwantedreaction when administered to an individual. A pharmaceuticalcomposition as disclosed herein is useful for medical and veterinaryapplications. A pharmaceutical composition may be administered to anindividual alone, or in combination with other supplementary activecompounds, agents, drugs or hormones.

In one embodiment, a composition can comprise a single ARE disclosedherein. In another embodiment, a composition can comprise a single AREdisclosed herein. In aspects of this embodiment, a composition disclosedherein comprises, e.g., one or more AREs, two or more AREs, three ormore AREs, four or more AREs or five or more AREs. In other aspects ofthis embodiment, a composition disclosed herein comprises, e.g., onlyone ARE, at most two AREs, at most three AREs, at most four AREs, or atmost five AREs. In yet other aspects of this embodiment, a compositiondisclosed herein comprises from, e.g., 1 to 2 AREs, 1 to 3 AREs, 1 to 4AREs, 1 to 5 AREs, 2 to 3 AREs, 2 to 4 AREs, 2 to 5 AREs, 3 to 4 AREs, 3to 5 AREs or 4 to 5 AREs.

The amount of one or more AREs in a pharmaceutical composition disclosedherein will generally range from about 0.01% to about 50% by weight ofthe total composition preferably from about 0.1% to about 50% by weightof total composition, more preferably from about 1% to about 50% byweight of the total composition.

In aspects of this embodiment, a composition disclosed herein comprisesan ARE in an amount of, e.g., 0.01%, 0.025%, 0.05%, 0.075%, 0.1%, 0.2%,0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.75%, 0.8%, 0.9%, 1%, 2%, 3%, 4%,5%, 6%, 7%, 8%. 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% byweight of the composition. In other aspects of this embodiment, acomposition disclosed herein comprises an ARE in an amount of, e.g., atleast 0.01%, at least 0.025%, at least 0.05%, at least 0.075%, at least0.1%, at least 0.25%, at least 0.5%, at least 0.75%, at least 1%, atleast 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least7%, at least 8%, at least 9%, least 10%, least 15%, least 20%, least25%, least 30%, least 35%, least 40%, at least 45%, or at least 50% byweight of the composition. In yet other aspects of this embodiment, acomposition disclosed herein comprises an ARE in an amount of, e.g., atmost 0.01%, at most 0.025%, at most 0.05%, at most 0.075%, at most 0.1%,at most 0.25%, at most 0.5%, at most 0.75%, at most 1%, at most 2%, atmost 3%, at most 4%, at most 5%, at most 6%, at most 7%, at most 8%, atmost 9%, at most 10%, at most 15%, at most 20%, at most 25%, at most30%, at most 35%, at most 40%, at most 45%, or at most 50% by weight ofthe composition.

In still other aspects of this embodiment, a composition disclosedherein comprises an ARE in an amount of from, e.g., 0.01% to about0.05%, 0.01% to about 0.075%, 0.01% to about 0.1%, about 0.1% to about0.5%, about 0.1% to about 0.75%, about 0.1% to about 1%, about 0.1% toabout 2%, about 0.1% to about 3%, about 0.1% to about 4%, about 0.1% toabout 5%, about 0.1% to about 6%, about 0.1% to about 7%, about 0.1% toabout 8%, about 0.1% to about 9%, about 0.1% to about 10%, about 0.1% toabout 15%, about 0.1% to about 20%, about 0.1% to about 25%, about 0.1%to about 30%, about 0.1% to about 35%, about 0.1% to about 40%, about0.25% to about 0.5%, about 0.25% to about 0.75%, about 0.25% to about1%, about 0.25% to about 2%, about 0.25% to about 3%, about 0.25% toabout 4%, about 0.25% to about 5%, about 0.25% to about 6%, about 0.25%to about 7%, about 0.25% to about 8%, about 0.25% to about 9%, about0.25% to about 10%, about 0.25% to about 15%, about 0.25% to about 20%,about 0.25% to about 25%, about 0.25% to about 30%, about 0.25% to about35%, about 0.25% to about 40%, about 0.5% to about 0.75%, about 0.5% toabout 1%, about 0.5% to about 2%, about 0.5% to about 3%, about 0.5% toabout 4%, about 0.5% to about 5%, about 0.5% to about 6%, about 0.5% toabout 7%, about 0.5% to about 8%, about 0.5% to about 9%, about 0.5% toabout 10%, about 0.5% to about 15%, about 0.5% to about 20%, about 0.5%to about 25%, about 0.5% to about 30%, about 0.5% to about 35%, about0.5% to about 40%, about 0.75% to about 1%, about 0.75% to about 2%,about 0.75% to about 3%, about 0.75% to about 4%, about 0.75% to about5%, about 0.75% to about 6%, about 0.75% to about 7%, about 0.75% toabout 8%, about 0.75% to about 9%, about 0.75% to about 10%, about 0.75%to about 15%, about 0.75% to about 20%, about 0.75% to about 25%, about0.75% to about 30%, about 0.75% to about 35%, about 0.75% to about 40%,about 1% to about 2%, about 1% to about 3%, about 1% to about 4%, about1% to about 5%, about 1% to about 6%, about 1% to about 7%, about 1% toabout 8%, about 1% to about 9%, about 1% to about 10%, about 1% to about15%, about 1% to about 20%, about 1% to about 25%, about 1% to about30%, about 1% to about 35%, about 1% to about 40%, about 2% to about 3%,about 2% to about 4%, about 2% to about 5%, about 2% to about 6%, about2% to about 7%, about 2% to about 8%, about 2% to about 9%, about 2% toabout 10%, about 2% to about 15%, about 2% to about 20%, about 2% toabout 25%, about 2% to about 30%, about 2% to about 35%, about 2% toabout 40%, about 3% to about 4%, about 3% to about 5%, about 3% to about6%, about 3% to about 7%, about 3% to about 8%, about 3% to about 9%,about 3% to about 10%, about 3% to about 15%, about 3% to about 20%,about 3% to about 25%, about 3% to about 30%, about 3% to about 35%,about 3% to about 40%, about 4% to about 5%, about 4% to about 6%, about4% to about 7%, about 4% to about 8%, about 4% to about 9%, about 4% toabout 10%, about 4% to about 15%, about 4% to about 20%, about 4% toabout 25%, about 4% to about 30%, about 4% to about 35%, about 4% toabout 40%, about 5% to about 6%, about 5% to about 7%, about 5% to about8%, about 5% to about 9%, about 5% to about 10%, about 5% to about 15%,about 5% to about 20%, about 5% to about 25%, about 5% to about 30%,about 5% to about 35%, about 5% to about 40%, about 6% to about 7%,about 6% to about 8%, about 6% to about 9%, about 6% to about 10%, about6% to about 15%, about 6% to about 20%, about 6% to about 25%, about 6%to about 30%, about 6% to about 35%, about 6% to about 40%, about 7% toabout 8%, about 7% to about 9%, about 7% to about 10%, about 7% to about15%, about 7% to about 20%, about 7% to about 25%, about 7% to about30%, about 7% to about 35%, about 7% to about 40%, about 8% to about 9%,about 8% to about 10%, about 8% to about 15%, about 8% to about 20%,about 8% to about 25%, about 8% to about 30%, about 8% to about 35%,about 8% to about 40%, about 9% to about 10%, about 9% to about 15%,about 9% to about 20%, about 9% to about 25%, about 9% to about 30%,about 9% to about 35%, about 9% to about 40%, about 10% to about 15%,about 10% to about 20%, about 10% to about 25%, about 10% to about 30%,about 10% to about 35%, about 10% to about 40%, about 10% to about 45%,about 10% to about 50%, about 15% to about 20%, about 15% to about 25%,about 15% to about 30%, about 15% to about 35%, about 15% to about 40%,about 15% to about 45%, about 15% to about 50%, about 20% to about 25%,about 20% to about 30%, about 20% to about 35%, about 20% to about 40%,about 20% to about 45%, about 20% to about 50%, about 25% to about 30%,about 25% to about 35%, about 25% to about 40%, about 25% to about 45%,about 30% to about 25%, about 30% to about 35%, about 30% to about 40%,about 30% to about 45%, about 30% to about 50%, about 35% to about 40%,about 35% to about 45%, about 35% to about 50%, about 40% to about 45%,about 40% to about 50%, or about 45% to about 50%, by weight of thecomposition.

In aspects of this embodiment, a composition disclosed herein comprisesan ARE in an amount of, e.g., about 1 μg, about 2 μg, about 3 μg, about4 μg, about 5 μg, about 6 μg, about 7 μg, about 8 μg, about 9 μg, about10 μg, about 15 μg, about 20 μg, about 25 μg, about 30 μg, about 35 μg,about 40 μg, about 45 μg, about 50 μg, about 55 μg, about 60 μg, about65 μg, about 70 μg, about 75 μg, about 80 μg, about 85 μg, about 90 μg,about 95 μg, about 100 μg, about 110 μg, about 120 μg, about 130 μg,about 140 μg, about 150 μg, about 160 μg, about 170 μg, about 180 μg,about 190 μg, about 200 μg, about 210 μg, about 220 μg, about 230 μg,about 240 μg, about 250 μg, 260 μg, about 270 μg, about 280 μg, about290 μg, about 300 μg, about 310 μg, about 320 μg, about 330 μg, about340 μg, about 350 μg, 360 μg, about 370 μg, about 380 μg, about 390 μg,about 400 μg, about 410 μg, about 420 μg, about 430 μg, about 440 μg,about 450 μg, 460 μg, about 470 μg, about 480 μg, about 490 μg, about500 μg, about 510 μg, about 520 μg, about 530 μg, about 540 μg, about550 μg, 560 μg, about 570 μg, about 580 μg, about 590 μg, about 600 μg,about 610 μg, about 620 μg, about 630 μg, about 640 μg, about 650 μg,660 μg, about 670 μg, about 680 μg, about 690 μg, about 700 μg, about710 μg, about 720 μg, about 730 μg, about 740 μg, about 750 μg, 760 μg,about 770 μg, about 780 μg, about 790 μg, about 800 μg, about 810 μg,about 820 μg, about 830 μg, about 840 μg, about 850 μg, 860 μg, about870 μg, about 880 μg, about 890 μg, about 900 μg, about 910 μg, about920 μg, about 930 μg, about 940 μg, about 950 μg, 960 μg, about 970 μg,about 980 μg, about 990 μg, or about 1,000 μg.

In other aspects of this embodiment, a composition disclosed hereincomprises an ARE in an amount of, e.g., at least 1 μg, at least 2 μg, atleast 3 μg, at least 4 μg, at least 5 μg, at least 6 μg, at least 7 μg,at least 8 μg, at least 9 μg, at least 10 μg, at least 15 μg, at least20 μg, at least 25 μg, at least 30 μg, at least 35 μg, at least 40 μg,at least 45 μg, at least 50 μg, at least 55 μg, at least 60 μg, at least65 μg, at least 70 μg, at least 75 μg, at least 80 μg, at least 85 μg,at least 90 μg, at least 95 μg, at least 100 μg, at least 110 μg, atleast 120 μg, at least 130 μg, at least 140 μg, at least 150 μg, atleast 160 μg, at least 170 μg, at least 180 μg, at least 190 μg, atleast 200 μg, at least 210 μg, at least 220 μg, at least 230 μg, atleast 240 μg, at least 250 μg, 260 μg, at least 270 μg, at least 280 μg,at least 290 μg, at least 300 μg, at least 310 μg, at least 320 μg, atleast 330 μg, at least 340 μg, at least 350 μg, 360 μg, at least 370 μg,at least 380 μg, at least 390 μg, at least 400 μg, at least 410 μg, atleast 420 μg, at least 430 μg, at least 440 μg, at least 450 μg, 460 μg,at least 470 μg, at least 480 μg, at least 490 μg, at least 500 μg, atleast 510 μg, at least 520 μg, at least 530 μg, at least 540 μg, atleast 550 μg, 560 μg, at least 570 μg, at least 580 μg, at least 590 μg,at least 600 μg, at least 610 μg, at least 620 μg, at least 630 μg, atleast 640 μg, at least 650 μg, 660 μg, at least 670 μg, at least 680 μg,at least 690 μg, at least 700 μg, at least 710 μg, at least 720 μg, atleast 730 μg, at least 740 μg, at least 750 μg, 760 μg, at least 770 μg,at least 780 μg, at least 790 μg, at least 800 μg, at least 810 μg, atleast 820 μg, at least 830 μg, at least 840 μg, at least 850 μg, 860 μg,at least 870 μg, at least 880 μg, at least 890 μg, at least 900 μg, atleast 910 μg, at least 920 μg, at least 930 μg, at least 940 μg, atleast 950 μg, 960 μg, at least 970 μg, at least 980 μg, at least 990 μg,or at least 1,000 μg.

In yet other aspects of this embodiment a composition disclosed hereincomprises an ARE in an amount of, e.g., at most 1 μg, at most 2 μg, atmost 3 μg, at most 4 μg, at most 5 μg, at most 6 μg, at most 7 μg, atmost 8 μg, at most 9 μg, at most 10 μg, at most 15 μg, at most 20 μg, atmost 25 μg, at most 30 μg, at most 35 μg, at most 40 μg, at most 45 μg,at most 50 μg, at most 55 μg, at most 60 μg, at most 65 μg, at most 70μg, at most 75 μg, at most 80 μg, at most 85 μg, at most 90 μg, at most95 μg, at most 100 μg, at most 110 μg, at most 120 μg, at most 130 μg,at most 140 μg, at most 150 μg, at most 160 μg, at most 170 μg, at most180 μg, at most 190 μg, at most 200 μg, at most 210 μg, at most 220 μg,at most 230 μg, at most 240 μg, at most 250 μg, 260 μg, at most 270 μg,at most 280 μg, at most 290 μg, at most 300 μg, at most 310 μg, at most320 μg, at most 330 μg, at most 340 μg, at most 350 μg, 360 μg, at most370 μg, at most 380 μg, at most 390 μg, at most 400 μg, at most 410 μg,at most 420 μg, at most 430 μg, at most 440 μg, at most 450 μg, 460 μg,at most 470 μg, at most 480 μg, at most 490 μg, at most 500 μg, at most510 μg, at most 520 μg, at most 530 μg, at most 540 μg, at most 550 μg,560 μg, at most 570 μg, at most 580 μg, at most 590 μg, at most 600 μg,at most 610 μg, at most 620 μg, at most 630 μg, at most 640 μg, at most650 μg, 660 μg, at most 670 μg, at most 680 μg, at most 690 μg, at most700 μg, at most 710 μg, at most 720 μg, at most 730 μg, at most 740 μg,at most 750 μg, 760 μg, at most 770 μg, at most 780 μg, at most 790 μg,at most 800 μg, at most 810 μg, at most 820 μg, at most 830 μg, at most840 μg, at most 850 μg, 860 μg, at most 870 μg, at most 880 μg, at most890 μg, at most 900 μg, at most 910 μg, at most 920 μg, at most 930 μg,at most 940 μg, at most 950 μg, 960 μg, at most 970 μg, at most 980 μg,at most 990 μg, or at most 1,000 μg.

In still other aspects of this embodiment, a composition disclosedherein comprises an ARE in an amount of, e.g., about 1 μg to about 10μg, about 1 μg to about 20 μg, about 1 μg to about 30 μg, about 1 μg toabout 40 μg, about 1 μg to about 50 μg, about 1 μg to about 60 μg, about1 μg to about 70 μg, about 1 μg to about 80 μg, about 1 μg to about 90μg, about 1 μg to about 100 μg, about 1 μg to about 110 μg, about 1 μgto about 120 μg, about 1 μg to about 130 μg, about 1 μg to about 140 μg,about 1 μg to about 150 μg, about 5 μg to about 10 μg, about 5 μg toabout 20 μg, about 5 μg to about 30 μg, about 5 μg to about 40 μg, about5 μg to about 50 μg, about 5 μg to about 60 μg, about 5 μg to about 70μg, about 5 μg to about 80 μg, about 5 μg to about 90 μg, about 5 μg toabout 100 μg, about 5 μg to about 110 μg, about 5 μg to about 120 μg,about 5 μg to about 130 μg, about 5 μg to about 140 μg, about 5 μg toabout 150 μg, about 10 μg to about 20 μg, about 10 μg to about 30 μg,about 10 μg to about 40 μg, about 10 μg to about 50 μg, about 10 μg toabout 60 μg, about 10 μg to about 70 μg, about 10 μg to about 80 μg,about 10 μg to about 90 μg, about 10 μg to about 100 μg, about 10 μg toabout 110 μg, about 10 μg to about 120 μg, about 10 μg to about 130 μg,about 10 μg to about 140 μg, about 10 μg to about 150 μg, about 10 μg toabout 175 μg, about 10 μg to about 200 μg, about 10 μg to about 225 μg,about 10 μg to about 250 μg, about 25 μg to about 50 μg, about 25 μg toabout 75 μg, about 25 μg to about 100 μg, about 25 μg to about 125 μg,about 25 μg to about 150 μg, about 25 μg to about 175 μg, about 25 μg toabout 200 μg, about 25 μg to about 225 μg, about 25 μg to about 250 μg,about 50 μg to about 75 μg, about 50 μg to about 100 μg, about 50 μg toabout 125 μg, about 50 μg to about 150 μg, about 50 μg to about 175 μg,about 50 μg to about 200 μg, about 50 μg to about 225 μg, about 50 μg toabout 250 μg, about 75 μg to about 100 μg, about 75 μg to about 125 μg,about 75 μg to about 150 μg, about 75 μg to about 175 μg, about 75 μg toabout 200 μg, about 75 μg to about 225 μg, or about 75 μg to about 250μg.

In still other aspects of this embodiment, a composition disclosedherein comprises an ARE in an amount of, e.g., about 100 μg to about 125μg, about 100 μg to about 150 μg, about 100 μg to about 175 μg, about100 μg to about 200 μg, about 100 μg to about 225 μg, about 100 μg toabout 250 μg, about 100 μg to about 275 μg, about 100 μg to about 300μg, about 100 μg to about 325 μg, about 100 μg to about 350 μg, about100 μg to about 375 μg, about 100 μg to about 400 μg, about 100 μg toabout 425 μg, about 100 μg to about 450 μg, about 100 μg to about 475μg, about 100 μg to about 500 μg, about 100 μg to about 525 μg, about100 μg to about 550 μg, about 100 μg to about 575 μg, about 100 μg toabout 600 μg, about 125 μg to about 150 μg, about 125 μg to about 175μg, about 125 μg to about 200 μg, about 125 μg to about 225 μg, about125 μg to about 250 μg, about 125 μg to about 275 μg, about 125 μg toabout 300 μg, about 125 μg to about 325 μg, about 125 μg to about 350μg, about 125 μg to about 375 μg, about 125 μg to about 400 μg, about125 μg to about 425 μg, about 125 μg to about 450 μg, about 125 μg toabout 475 μg, about 125 μg to about 500 μg, about 125 μg to about 525μg, about 125 μg to about 550 μg, about 125 μg to about 575 μg, about125 μg to about 600 μg, about 150 μg to about 175 μg, about 150 μg toabout 200 μg, about 150 μg to about 225 μg, about 150 μg to about 250μg, about 150 μg to about 275 μg, about 150 μg to about 300 μg, about150 μg to about 325 μg, about 150 μg to about 350 μg, about 150 μg toabout 375 μg, about 150 μg to about 400 μg, about 150 μg to about 425μg, about 150 μg to about 450 μg, about 150 μg to about 475 μg, about150 μg to about 500 μg, about 150 μg to about 525 μg, about 150 μg toabout 550 μg, about 150 μg to about 575 μg, about 150 μg to about 600μg, about 200 μg to about 225 μg, about 200 μg to about 250 μg, about200 μg to about 275 μg, about 200 μg to about 300 μg, about 200 μg toabout 325 μg, about 200 μg to about 350 μg, about 200 μg to about 375μg, about 200 μg to about 400 μg, about 200 μg to about 425 μg, about200 μg to about 450 μg, about 200 μg to about 475 μg, about 200 μg toabout 500 μg, about 200 μg to about 525 μg, about 200 μg to about 550μg, about 200 μg to about 575 μg, about 200 μg to about 600 μg, about200 μg to about 625 μg, about 200 μg to about 650 μg, about 200 μg toabout 675 μg, about 200 μg to about 700 μg, about 200 μg to about 725μg, about 200 μg to about 750 μg, about 200 μg to about 775 μg, about200 μg to about 800 μg, about 200 μg to about 825 μg, about 200 μg toabout 850 μg, about 200 μg to about 875 μg, about 200 μg to about 900μg, about 200 μg to about 925 μg, about 200 μg to about 950 μg, about200 μg to about 975 μg, or about 200 μg to about 1,000 μg.

In still other aspects of this embodiment, a composition disclosedherein comprises an ARE in an amount of, e.g., about 250 μg to about 275μg, about 250 μg to about 300 μg, about 250 μg to about 325 μg, about250 μg to about 350 μg, about 250 μg to about 375 μg, about 250 μg toabout 400 μg, about 250 μg to about 425 μg, about 250 μg to about 450μg, about 250 μg to about 475 μg, about 250 μg to about 500 μg, about250 μg to about 525 μg, about 250 μg to about 550 μg, about 250 μg toabout 575 μg, about 250 μg to about 600 μg, about 250 μg to about 625μg, about 250 μg to about 650 μg, about 250 μg to about 675 μg, about250 μg to about 700 μg, about 250 μg to about 725 μg, about 250 μg toabout 750 μg, about 250 μg to about 775 μg, about 250 μg to about 800μg, about 250 μg to about 825 μg, about 250 μg to about 850 μg, about250 μg to about 875 μg, about 250 μg to about 900 μg, about 250 μg toabout 925 μg, about 250 μg to about 950 μg, about 250 μg to about 975μg, about 250 μg to about 1,000 μg, about 300 μg to about 325 μg, about300 μg to about 350 μg, about 300 μg to about 375 μg, about 300 μg toabout 400 μg, about 300 μg to about 425 μg, about 300 μg to about 450μg, about 300 μg to about 475 μg, about 300 μg to about 500 μg, about300 μg to about 525 μg, about 300 μg to about 550 μg, about 300 μg toabout 575 μg, about 300 μg to about 600 μg, about 300 μg to about 625μg, about 300 μg to about 650 μg, about 300 μg to about 675 μg, about300 μg to about 700 μg, about 300 μg to about 725 μg, about 300 μg toabout 750 μg, about 300 μg to about 775 μg, about 300 μg to about 800μg, about 300 μg to about 825 μg, about 300 μg to about 850 μg, about300 μg to about 875 μg, about 300 μg to about 900 μg, about 300 μg toabout 925 μg, about 300 μg to about 950 μg, about 300 μg to about 975μg, about 300 μg to about 1,000 μg, about 400 μg to about 425 μg, about400 μg to about 450 μg, about 400 μg to about 475 μg, about 400 μg toabout 500 μg, about 400 μg to about 525 μg, about 400 μg to about 550μg, about 400 μg to about 575 μg, about 400 μg to about 600 μg, about400 μg to about 625 μg, about 400 μg to about 650 μg, about 400 μg toabout 675 μg, about 400 μg to about 700 μg, about 400 μg to about 725μg, about 400 μg to about 750 μg, about 400 μg to about 775 μg, about400 μg to about 800 μg, about 400 μg to about 825 μg, about 400 μg toabout 850 μg, about 400 μg to about 875 μg, about 400 μg to about 900μg, about 400 μg to about 925 μg, about 400 μg to about 950 μg, about400 μg to about 975 μg, or about 400 μg to about 1,000 μg.

In still other aspects of this embodiment, a composition disclosedherein comprises an ARE in an amount of, e.g., about 500 μg to about 525μg, about 500 μg to about 550 μg, about 500 μg to about 575 μg, about500 μg to about 600 μg, about 500 μg to about 625 μg, about 500 μg toabout 650 μg, about 500 μg to about 675 μg, about 500 μg to about 700μg, about 500 μg to about 725 μg, about 500 μg to about 750 μg, about500 μg to about 775 μg, about 500 μg to about 800 μg, about 500 μg toabout 825 μg, about 500 μg to about 850 μg, about 500 μg to about 875μg, about 500 μg to about 900 μg, about 500 μg to about 925 μg, about500 μg to about 950 μg, about 500 μg to about 975 μg, about 500 μg toabout 1,000 μg, about 600 μg to about 625 μg, about 600 μg to about 650μg, about 600 μg to about 675 μg, about 600 μg to about 700 μg, about600 μg to about 725 μg, about 600 μg to about 750 μg, about 600 μg toabout 775 μg, about 600 μg to about 800 μg, about 600 μg to about 825μg, about 600 μg to about 850 μg, about 600 μg to about 875 μg, about600 μg to about 900 μg, about 600 μg to about 925 μg, about 600 μg toabout 950 μg, about 600 μg to about 975 μg, about 600 μg to about 1,000μg, about 700 μg to about 725 μg, about 700 μg to about 750 μg, about700 μg to about 775 μg, about 700 μg to about 800 μg, about 700 μg toabout 825 μg, about 700 μg to about 850 μg, about 700 μg to about 875μg, about 700 μg to about 900 μg, about 700 μg to about 925 μg, about700 μg to about 950 μg, about 700 μg to about 975 μg, about 700 μg toabout 1,000 μg, about 800 μg to about 825 μg, about 800 μg to about 850μg, about 800 μg to about 875 μg, about 800 μg to about 900 μg, about800 μg to about 925 μg, about 800 μg to about 950 μg, about 800 μg toabout 975 μg, or about 800 μg to about 1,000 μg.

In aspects of this embodiment, a composition disclosed herein comprisesan ARE in an amount of, e.g., about 1 mg, about 2 mg, about 3 mg, about4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg,about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg,about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg,about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg,about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg,about 240 mg, about 250 mg, 260 mg, about 270 mg, about 280 mg, about290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about340 mg, about 350 mg, 360 mg, about 370 mg, about 380 mg, about 390 mg,about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg,about 450 mg, 460 mg, about 470 mg, about 480 mg, about 490 mg, about500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about550 mg, 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg,about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg,660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, 760 mg,about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg,about 820 mg, about 830 mg, about 840 mg, about 850 mg, 860 mg, about870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about920 mg, about 930 mg, about 940 mg, about 950 mg, 960 mg, about 970 mg,about 980 mg, about 990 mg, or about 1,000 mg.

In other aspects of this embodiment, a composition disclosed hereincomprises an ARE in an amount of, e.g., at least 1 mg, at least 2 mg, atleast 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg,at least 8 mg, at least 9 mg, at least 10 mg, at least 15 mg, at least20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg,at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg,at least 90 mg, at least 95 mg, at least 100 mg, at least 110 mg, atleast 120 mg, at least 130 mg, at least 140 mg, at least 150 mg, atleast 160 mg, at least 170 mg, at least 180 mg, at least 190 mg, atleast 200 mg, at least 210 mg, at least 220 mg, at least 230 mg, atleast 240 mg, at least 250 mg, 260 mg, at least 270 mg, at least 280 mg,at least 290 mg, at least 300 mg, at least 310 mg, at least 320 mg, atleast 330 mg, at least 340 mg, at least 350 mg, 360 mg, at least 370 mg,at least 380 mg, at least 390 mg, at least 400 mg, at least 410 mg, atleast 420 mg, at least 430 mg, at least 440 mg, at least 450 mg, 460 mg,at least 470 mg, at least 480 mg, at least 490 mg, at least 500 mg, atleast 510 mg, at least 520 mg, at least 530 mg, at least 540 mg, atleast 550 mg, 560 mg, at least 570 mg, at least 580 mg, at least 590 mg,at least 600 mg, at least 610 mg, at least 620 mg, at least 630 mg, atleast 640 mg, at least 650 mg, 660 mg, at least 670 mg, at least 680 mg,at least 690 mg, at least 700 mg, at least 710 mg, at least 720 mg, atleast 730 mg, at least 740 mg, at least 750 mg, 760 mg, at least 770 mg,at least 780 mg, at least 790 mg, at least 800 mg, at least 810 mg, atleast 820 mg, at least 830 mg, at least 840 mg, at least 850 mg, 860 mg,at least 870 mg, at least 880 mg, at least 890 mg, at least 900 mg, atleast 910 mg, at least 920 mg, at least 930 mg, at least 940 mg, atleast 950 mg, 960 mg, at least 970 mg, at least 980 mg, at least 990 mg,or at least 1,000 mg.

In yet other aspects of this embodiment, a composition disclosed hereincomprises an ARE in an amount of, e.g., at most 1 mg, at most 2 mg, atmost 3 mg, at most 4 mg, at most 5 mg, at most 6 mg, at most 7 mg, atmost 8 mg, at most 9 mg, at most 10 mg, at most 15 mg, at most 20 mg, atmost 25 mg, at most 30 mg, at most 35 mg, at most 40 mg, at most 45 mg,at most 50 mg, at most 55 mg, at most 60 mg, at most 65 mg, at most 70mg, at most 75 mg, at most 80 mg, at most 85 mg, at most 90 mg, at most95 mg, at most 100 mg, at most 110 mg, at most 120 mg, at most 130 mg,at most 140 mg, at most 150 mg, at most 160 mg, at most 170 mg, at most180 mg, at most 190 mg, at most 200 mg, at most 210 mg, at most 220 mg,at most 230 mg, at most 240 mg, at most 250 mg, 260 mg, at most 270 mg,at most 280 mg, at most 290 mg, at most 300 mg, at most 310 mg, at most320 mg, at most 330 mg, at most 340 mg, at most 350 mg, 360 mg, at most370 mg, at most 380 mg, at most 390 mg, at most 400 mg, at most 410 mg,at most 420 mg, at most 430 mg, at most 440 mg, at most 450 mg, 460 mg,at most 470 mg, at most 480 mg, at most 490 mg, at most 500 mg, at most510 mg, at most 520 mg, at most 530 mg, at most 540 mg, at most 550 mg,560 mg, at most 570 mg, at most 580 mg, at most 590 mg, at most 600 mg,at most 610 mg, at most 620 mg, at most 630 mg, at most 640 mg, at most650 mg, 660 mg, at most 670 mg, at most 680 mg, at most 690 mg, at most700 mg, at most 710 mg, at most 720 mg, at most 730 mg, at most 740 mg,at most 750 mg, 760 mg, at most 770 mg, at most 780 mg, at most 790 mg,at most 800 mg, at most 810 mg, at most 820 mg, at most 830 mg, at most840 mg, at most 850 mg, 860 mg, at most 870 mg, at most 880 mg, at most890 mg, at most 900 mg, at most 910 mg, at most 920 mg, at most 930 mg,at most 940 mg, at most 950 mg, 960 mg, at most 970 mg, at most 980 mg,at most 990 mg, or at most 1,000 mg.

In still other aspects of this embodiment, a composition disclosedherein comprises an ARE in an amount of, e.g., about 1 mg to about 10mg, about 1 mg to about 20 mg, about 1 mg to about 30 mg, about 1 mg toabout 40 mg, about 1 mg to about 50 mg, about 1 mg to about 60 mg, about1 mg to about 70 mg, about 1 mg to about 80 mg, about 1 mg to about 90mg, about 1 mg to about 100 mg, about 1 mg to about 110 mg, about 1 mgto about 120 mg, about 1 mg to about 130 mg, about 1 mg to about 140 mg,about 1 mg to about 150 mg, about 5 mg to about 10 mg, about 5 mg toabout 20 mg, about 5 mg to about 30 mg, about 5 mg to about 40 mg, about5 mg to about 50 mg, about 5 mg to about 60 mg, about 5 mg to about 70mg, about 5 mg to about 80 mg, about 5 mg to about 90 mg, about 5 mg toabout 100 mg, about 5 mg to about 110 mg, about 5 mg to about 120 mg,about 5 mg to about 130 mg, about 5 mg to about 140 mg, about 5 mg toabout 150 mg, about 10 mg to about 20 mg, about 10 mg to about 30 mg,about 10 mg to about 40 mg, about 10 mg to about 50 mg, about 10 mg toabout 60 mg, about 10 mg to about 70 mg, about 10 mg to about 80 mg,about 10 mg to about 90 mg, about 10 mg to about 100 mg, about 10 mg toabout 110 mg, about 10 mg to about 120 mg, about 10 mg to about 130 mg,about 10 mg to about 140 mg, about 10 mg to about 150 mg, about 10 mg toabout 175 mg, about 10 mg to about 200 mg, about 10 mg to about 225 mg,about 10 mg to about 250 mg, about 25 mg to about 50 mg, about 25 mg toabout 75 mg, about 25 mg to about 100 mg, about 25 mg to about 125 mg,about 25 mg to about 150 mg, about 25 mg to about 175 mg, about 25 mg toabout 200 mg, about 25 mg to about 225 mg, about 25 mg to about 250 mg,about 50 mg to about 75 mg, about 50 mg to about 100 mg, about 50 mg toabout 125 mg, about 50 mg to about 150 mg, about 50 mg to about 175 mg,about 50 mg to about 200 mg, about 50 mg to about 225 mg, about 50 mg toabout 250 mg, about 75 mg to about 100 mg, about 75 mg to about 125 mg,about 75 mg to about 150 mg, about 75 mg to about 175 mg, about 75 mg toabout 200 mg, about 75 mg to about 225 mg, or about 75 mg to about 250mg.

In still other aspects of this embodiment, a composition disclosedherein comprises an ARE in an amount of, e.g., about 100 mg to about 125mg, about 100 mg to about 150 mg, about 100 mg to about 175 mg, about100 mg to about 200 mg, about 100 mg to about 225 mg, about 100 mg toabout 250 mg, about 100 mg to about 275 mg, about 100 mg to about 300mg, about 100 mg to about 325 mg, about 100 mg to about 350 mg, about100 mg to about 375 mg, about 100 mg to about 400 mg, about 100 mg toabout 425 mg, about 100 mg to about 450 mg, about 100 mg to about 475mg, about 100 mg to about 500 mg, about 100 mg to about 525 mg, about100 mg to about 550 mg, about 100 mg to about 575 mg, about 100 mg toabout 600 mg, about 125 mg to about 150 mg, about 125 mg to about 175mg, about 125 mg to about 200 mg, about 125 mg to about 225 mg, about125 mg to about 250 mg, about 125 mg to about 275 mg, about 125 mg toabout 300 mg, about 125 mg to about 325 mg, about 125 mg to about 350mg, about 125 mg to about 375 mg, about 125 mg to about 400 mg, about125 mg to about 425 mg, about 125 mg to about 450 mg, about 125 mg toabout 475 mg, about 125 mg to about 500 mg, about 125 mg to about 525mg, about 125 mg to about 550 mg, about 125 mg to about 575 mg, about125 mg to about 600 mg, about 150 mg to about 175 mg, about 150 mg toabout 200 mg, about 150 mg to about 225 mg, about 150 mg to about 250mg, about 150 mg to about 275 mg, about 150 mg to about 300 mg, about150 mg to about 325 mg, about 150 mg to about 350 mg, about 150 mg toabout 375 mg, about 150 mg to about 400 mg, about 150 mg to about 425mg, about 150 mg to about 450 mg, about 150 mg to about 475 mg, about150 mg to about 500 mg, about 150 mg to about 525 mg, about 150 mg toabout 550 mg, about 150 mg to about 575 mg, about 150 mg to about 600mg, about 200 mg to about 225 mg, about 200 mg to about 250 mg, about200 mg to about 275 mg, about 200 mg to about 300 mg, about 200 mg toabout 325 mg, about 200 mg to about 350 mg, about 200 mg to about 375mg, about 200 mg to about 400 mg, about 200 mg to about 425 mg, about200 mg to about 450 mg, about 200 mg to about 475 mg, about 200 mg toabout 500 mg, about 200 mg to about 525 mg, about 200 mg to about 550mg, about 200 mg to about 575 mg, about 200 mg to about 600 mg, about200 mg to about 625 mg, about 200 mg to about 650 mg, about 200 mg toabout 675 mg, about 200 mg to about 700 mg, about 200 mg to about 725mg, about 200 mg to about 750 mg, about 200 mg to about 775 mg, about200 mg to about 800 mg, about 200 mg to about 825 mg, about 200 mg toabout 850 mg, about 200 mg to about 875 mg, about 200 mg to about 900mg, about 200 mg to about 925 mg, about 200 mg to about 950 mg, about200 mg to about 975 mg, or about 200 mg to about 1,000 mg.

In still other aspects of this embodiment, a composition disclosedherein comprises an ARE in an amount of, e.g., about 250 mg to about 275mg, about 250 mg to about 300 mg, about 250 mg to about 325 mg, about250 mg to about 350 mg, about 250 mg to about 375 mg, about 250 mg toabout 400 mg, about 250 mg to about 425 mg, about 250 mg to about 450mg, about 250 mg to about 475 mg, about 250 mg to about 500 mg, about250 mg to about 525 mg, about 250 mg to about 550 mg, about 250 mg toabout 575 mg, about 250 mg to about 600 mg, about 250 mg to about 625mg, about 250 mg to about 650 mg, about 250 mg to about 675 mg, about250 mg to about 700 mg, about 250 mg to about 725 mg, about 250 mg toabout 750 mg, about 250 mg to about 775 mg, about 250 mg to about 800mg, about 250 mg to about 825 mg, about 250 mg to about 850 mg, about250 mg to about 875 mg, about 250 mg to about 900 mg, about 250 mg toabout 925 mg, about 250 mg to about 950 mg, about 250 mg to about 975mg, about 250 mg to about 1,000 mg, about 300 mg to about 325 mg, about300 mg to about 350 mg, about 300 mg to about 375 mg, about 300 mg toabout 400 mg, about 300 mg to about 425 mg, about 300 mg to about 450mg, about 300 mg to about 475 mg, about 300 mg to about 500 mg, about300 mg to about 525 mg, about 300 mg to about 550 mg, about 300 mg toabout 575 mg, about 300 mg to about 600 mg, about 300 mg to about 625mg, about 300 mg to about 650 mg, about 300 mg to about 675 mg, about300 mg to about 700 mg, about 300 mg to about 725 mg, about 300 mg toabout 750 mg, about 300 mg to about 775 mg, about 300 mg to about 800mg, about 300 mg to about 825 mg, about 300 mg to about 850 mg, about300 mg to about 875 mg, about 300 mg to about 900 mg, about 300 mg toabout 925 mg, about 300 mg to about 950 mg, about 300 mg to about 975mg, about 300 mg to about 1,000 mg, about 400 mg to about 425 mg, about400 mg to about 450 mg, about 400 mg to about 475 mg, about 400 mg toabout 500 mg, about 400 mg to about 525 mg, about 400 mg to about 550mg, about 400 mg to about 575 mg, about 400 mg to about 600 mg, about400 mg to about 625 mg, about 400 mg to about 650 mg, about 400 mg toabout 675 mg, about 400 mg to about 700 mg, about 400 mg to about 725mg, about 400 mg to about 750 mg, about 400 mg to about 775 mg, about400 mg to about 800 mg, about 400 mg to about 825 mg, about 400 mg toabout 850 mg, about 400 mg to about 875 mg, about 400 mg to about 900mg, about 400 mg to about 925 mg, about 400 mg to about 950 mg, about400 mg to about 975 mg, or about 400 mg to about 1,000 mg.

In still other aspects of this embodiment, a composition disclosedherein comprises an ARE in an amount of, e.g., about 500 mg to about 525mg, about 500 mg to about 550 mg, about 500 mg to about 575 mg, about500 mg to about 600 mg, about 500 mg to about 625 mg, about 500 mg toabout 650 mg, about 500 mg to about 675 mg, about 500 mg to about 700mg, about 500 mg to about 725 mg, about 500 mg to about 750 mg, about500 mg to about 775 mg, about 500 mg to about 800 mg, about 500 mg toabout 825 mg, about 500 mg to about 850 mg, about 500 mg to about 875mg, about 500 mg to about 900 mg, about 500 mg to about 925 mg, about500 mg to about 950 mg, about 500 mg to about 975 mg, about 500 mg toabout 1,000 mg, about 600 mg to about 625 mg, about 600 mg to about 650mg, about 600 mg to about 675 mg, about 600 mg to about 700 mg, about600 mg to about 725 mg, about 600 mg to about 750 mg, about 600 mg toabout 775 mg, about 600 mg to about 800 mg, about 600 mg to about 825mg, about 600 mg to about 850 mg, about 600 mg to about 875 mg, about600 mg to about 900 mg, about 600 mg to about 925 mg, about 600 mg toabout 950 mg, about 600 mg to about 975 mg, about 600 mg to about 1,000mg, about 700 mg to about 725 mg, about 700 mg to about 750 mg, about700 mg to about 775 mg, about 700 mg to about 800 mg, about 700 mg toabout 825 mg, about 700 mg to about 850 mg, about 700 mg to about 875mg, about 700 mg to about 900 mg, about 700 mg to about 925 mg, about700 mg to about 950 mg, about 700 mg to about 975 mg, about 700 mg toabout 1,000 mg, about 800 mg to about 825 mg, about 800 mg to about 850mg, about 800 mg to about 875 mg, about 800 mg to about 900 mg, about800 mg to about 925 mg, about 800 mg to about 950 mg, about 800 mg toabout 975 mg, or about 800 mg to about 1,000 mg.

A pharmaceutical composition disclosed herein can optionally include apharmaceutically acceptable carrier that facilitates processing of anARE into pharmaceutically acceptable compositions. A pharmacologicallyacceptable carrier is synonymous with “pharmacological carrier” andrefers to any carrier that has substantially no long term or permanentdetrimental effect when administered and encompasses terms such aspharmacologically acceptable vehicle, stabilizer, diluent, additive,auxiliary, or excipient. Such a carrier generally is mixed with anactive compound or permitted to dilute or enclose the active compoundand can be a solid, semi-solid, or liquid agent. It is understood thatthe active ingredients can be soluble or can be delivered as asuspension in the desired carrier or diluent.

In one embodiment, a single pharmaceutically acceptable carrier ispresent in a composition disclosed herein. In another embodiment, aplurality of pharmaceutically acceptable carriers are present in acomposition disclosed herein. In aspects of this embodiment, acomposition disclosed herein comprises, e.g., one or more, two or more,three or more, four or more or five or more pharmaceutically acceptablecarriers. In other aspects of this embodiment, a composition disclosedherein comprises, e.g., only one, at most two, at most three, at mostfour, or at most five pharmaceutically acceptable carriers. In yet otheraspects of this embodiment, a composition disclosed herein comprisesfrom, e.g., 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to4, 3 to 5 or 4 to 5 pharmaceutically acceptable carriers.

In another embodiment, a composition disclosed herein comprises anamount of pharmaceutically acceptable carrier that provides a desiredformulative or beneficial effect to a pharmaceutical compositiondisclosed herein. In aspects of this embodiment, a composition disclosedherein comprises a pharmaceutically acceptable carrier in an amount of,e.g., at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90%, at least95%, at least 96%, at least 97%, at least 98% or at least 99% by weightof the composition. In other aspects of this embodiment, a compositiondisclosed herein comprises a pharmaceutically acceptable carrier in anamount of, e.g., at most 25%, at most 30%, at most 35%, at most 40%, atmost 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 95%, atmost 96%, at most 97%, at most 98% or at most 99% by weight of thecomposition. In yet other aspects of this embodiment, a compositiondisclosed herein comprises a pharmaceutically acceptable carrier in anamount of from, e.g., about 25% to about 50%, about 25% to about 75%,about 25% to about 90%, about 25% to about 95%, about 25% to about 96%,about 25% to about 97%, about 25% to about 98%, about 25% to about 99%,about 50% to about 75%, about 50% to about 90%, about 50% to about 95%,about 50% to about 96%, about 50% to about 97%, about 50% to about 98%,about 50% to about 99%, about 75% to about 80%, about 75% to about 85%,about 75% to about 90%, about 75% to about 95%, about 75% to about 96%,about 75% to about 97%, about 75% to about 98%, about 75% to about 99%,about 80% to about 85%, about 80% to about 90%, about 80% to about 95%,about 80% to about 96%, about 80% to about 97%, about 80% to about 98%,about 80% to about 99%, about 85% to about 90%, about 85% to about 95%,about 85% to about 96%, about 85% to about 97%, about 85% to about 98%,about 85% to about 99%, about 90% to about 95%, about 90% to about 96%,about 90% to about 97%, about 90% to about 98%, about 90% to about 99%,or about 95% to about 99%, by weight of the composition.

A pharmaceutical composition disclosed herein may further comprise oneor more pharmaceutically acceptable components (or pharmaceuticalcomponents), including, without limitation, buffers, preservatives,tonicity adjusters, salts, antioxidants, osmolality adjusting agents,physiological substances, pharmacological substances, bulking agents,viscosity agents, surfactants, emulsifying agents, wetting agents,sweetening or flavoring agents, and the like. Various buffers and meansfor adjusting pH can be used to prepare a pharmaceutical compositiondisclosed herein, provided that the resulting preparation ispharmaceutically acceptable. Such buffers include, without limitation,acetate buffers, citrate buffers, phosphate buffers, neutral bufferedsaline, phosphate buffered saline and borate buffers. It is understoodthat acids or bases can be used to adjust the pH of a composition asneeded. Pharmaceutically acceptable antioxidants include, withoutlimitation, sodium metabisulfite, sodium thiosulfate, acetylcysteine,butylated hydroxyanisole and butylated hydroxytoluene. Usefulpreservatives include, without limitation, benzalkonium chloride,chlorobutanol, chlorhexidine, thimerosal, a parahydroxybenzoic acid suchas, e.g., like methyl-, propyl-, or butyl-parahydroxybenzoic acid, aphenylmercuric salt such as, e.g., nitrate, chloride, acetate, andborate, a stabilized oxy chloro composition, such as, e.g., PURITE® andchelants, such as, e.g., EDTA, DTPA or DTPA-bisamide, calcium DTPA, andCaNaDTPA-bisamide. Tonicity adjustors useful in a pharmaceuticalcomposition include, without limitation, salts such as, e.g., sodiumchloride, potassium chloride, mannitol or glycerin and otherpharmaceutically acceptable tonicity adjustor. A bulking agent orviscosity agent useful in a pharmaceutical composition include, withoutlimitation, a polysaccharide, such as, e.g., methylcellulose,mucopolysaccharides, e.g., hyaluronic acid and chondroitin sulfate, orpolyalcohol, e.g., polyvinylalcohol. Various slow releasing gels andmatrices may also be employed as well as soluble and insoluble ocularinserts, for instance, based on substances forming in-situ gels. Thepharmaceutical composition may be provided as a salt and can be formedwith many acids, including but not limited to, hydrochloric, sulfuric,acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be moresoluble in aqueous or other protonic solvents than are the correspondingfree base forms. It is understood that these and other substances knownin the art of pharmacology can be included in a pharmaceuticalcomposition.

A pharmaceutical composition disclosed herein can be formulated into anyform that enables topical application of an ARE disclosed herein in amanner that achieves a desired beneficial effect. A topical applicationrefers to the use of at least ARE described herein, incorporated in asuitable pharmaceutical carrier, and applied at a site of skin and/orthinning hair or baldness for exertion of local action. Accordingly,such topical compositions include those pharmaceutical forms in whichthe at least one ARE is applied externally by direct contact with theskin surface to be treated.

In one embodiment, a composition disclosed herein can be formulatedinto, e.g., a single phase formulation or a biphasic formulationcomprising a medium phase and a dispersed phase. In another embodiment,a composition disclosed herein can be formulated into, e.g., a liquidcomposition, a colloidal composition, a semi-solid composition, or asolid composition. In another embodiment, a composition disclosed hereincan be formulated into, e.g., a liquid aerosol, a foam, an emulsion, agel, a sol, or a solid sol. In another embodiment, a compositiondisclosed herein can be formulated into, e.g., a spray, a liquidaerosol, a wash, an aftershave, a perfume, a lotion, a cream, a salve, awaxing composition, a mousse, a shampoo, a conditioner, an ointment, aliniment, a paste, a jelly, a soap, a suspension, or an emollient.Various gels and matrices for slow release delivery may also be employedas well as soluble and insoluble ocular inserts, for instance, based onsubstances forming in-situ gels.

In one embodiment, a pharmaceutical composition disclosed herein ismixed with a dermatologically compatible vehicle or carrier. The vehiclewhich may be employed for preparing compositions may comprise, forexample, aqueous solutions such as e.g., physiological salines, oilsolutions or ointments. The vehicle furthermore may containdermatologically compatible preservatives such as e.g., benzalkoniumchloride, surfactants like e.g., polysorbate 80, liposomes or polymers,for example, methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidoneand hyaluronic acid; these may be used for increasing the viscosity.Furthermore, it is also possible to use soluble or insoluble druginserts when the drug is to be administered.

In one embodiment, a pharmaceutical composition disclosed hereincomprising 0.1% to 10% of a compound disclosed herein, 20% to 40%denatured alcohol, 40% to 60% isopropyl myristate, and 10% to 30%Transcutol. In aspects of this embodiment, a pharmaceutical compositiondisclosed herein comprising 0.25% to 8% of a compound disclosed herein,23% to 37% denatured alcohol, 43% to 57% isopropyl myristate, and 13% to27% Transcutol. In other aspects of this embodiment, a pharmaceuticalcomposition disclosed herein comprising 0.5% to 5% of a compounddisclosed herein, 25% to 35% denatured alcohol, 45% to 55% isopropylmyristate, and 15% to 25% Transcutol. In yet other aspects of thisembodiment, a pharmaceutical composition disclosed herein comprising0.75% to 3% of a compound disclosed herein, 27% to 32% denaturedalcohol, 47% to 52% isopropyl myristate, and 17% to 22% Transcutol. Instill other aspects of this embodiment, a pharmaceutical compositiondisclosed herein comprising 1% to 2% of a compound disclosed herein, 29%to 31% denatured alcohol, 48% to 50% isopropyl myristate, and 19% to 21%Transcutol.

In one embodiment, a pharmaceutical composition disclosed hereincomprising 0.1% to 10% of any one of Compounds 37 to 52, or anycombination thereof, 20% to 40% denatured alcohol, 40% to 60% isopropylmyristate, and 10% to 30% Transcutol. In aspects of this embodiment, apharmaceutical composition disclosed herein comprising 0.25% to 8% ofany one of Compounds 37 to 52, or any combination thereof, 23% to 37%denatured alcohol, 43% to 57% isopropyl myristate, and 13% to 27%Transcutol. In other aspects of this embodiment, a pharmaceuticalcomposition disclosed herein comprising 0.5% to 5% of any one ofCompounds 37 to 52, or any combination thereof, 25% to 35% denaturedalcohol, 45% to 55% isopropyl myristate, and 15% to 25% Transcutol. Inyet other aspects of this embodiment, a pharmaceutical compositiondisclosed herein comprising 0.75% to 3% of any one of Compounds 37 to52, or any combination thereof, 27% to 32% denatured alcohol, 47% to 52%isopropyl myristate, and 17% to 22% Transcutol. In still other aspectsof this embodiment, a pharmaceutical composition disclosed hereincomprising 1% to 2% of any one of Compounds 37 to 52, or any combinationthereof, 29% to 31% denatured alcohol, 48% to 50% isopropyl myristate,and 19% to 21% Transcutol.

In one embodiment, a pharmaceutical composition disclosed herein can behoused in containers suitable for dispensing the composition. Thecontainer can be a vial, bottle, tube, etc. In certain embodiments, thecontainer will be a squeezable in order to release the compositiontherein. The container can have a lid, which may snap, twist, etc. onand off. The container should be such that the sterility of thecomposition therein is maintained. In certain embodiments, the containerwill have a safety seal prior to opening. In one embodiment, a containermay hold from about 1 mL to about 50 mL of the composition disclosedherein. In aspects of this embodiment, a container may hold from, e.g.,1 mL to 5 mL, 1 mL to 10 mL, 1 mL to 15 mL, 1 mL to 20 mL, 1 mL to 25mL, 1 mL to 30 mL, 1 mL to 35 mL, 1 mL to 40 mL, 1 mL to 45 mL, 1 mL to50 mL, 2 mL to 5 mL, 2 mL to 10 mL, 2 mL to 15 mL, 2 mL to 20 mL, 2 mLto 25 mL, 2 mL to 30 mL, 2 mL to 35 mL, 2 mL to 40 mL, 2 mL to 45 mL, 2mL to 50 mL, 3 mL to 5 mL, 3 mL to 10 mL, 3 mL to 15 mL, 3 mL to 20 mL,3 mL to 25 mL, 3 mL to 30 mL, 3 mL to 35 mL, 3 mL to 40 mL, 3 mL to 45mL, 3 mL to 50 mL, 5 mL to 10 mL, 5 mL to 15 mL, 5 mL to 20 mL, 5 mL to25 mL, 5 mL to 30 mL, 5 mL to 35 mL, 5 mL to 40 mL, 5 mL to 45 mL, 5 mLto 50 mL, 10 mL to 20 ml, 10 mL to 30 mL, 10 mL, 40 mL, 10 mL to 50 mL,20 mL to 30 mL, 20 mL, 40 mL, 20 mL to 50 mL, 30 mL, 40 mL, 30 mL to 50mL, or 40 mL, 50 mL.

A pharmaceutical composition disclosed herein can be provided in a kit.A kit can comprise a delivery system having one or more of an applicatorbrush, porous foam swab or pad, hollow tube, dipstick, or a combinationthereof. In certain embodiments, the delivery system comprises aplurality of applicator brushes that have filaments coated with alubricity enhancing agent. The lubricity enhancing agent can be apolymer that is coated onto the filaments in order to control therelease of the composition from the brush, that is, the composition isnot released from the brush until it makes contact with the skin surfaceand the rate of release is such that a therapeutically appropriateamount of a composition is released from the brush onto a skin surface.The applicator brushes of the kit are useful for applying the hairgrowth enhancing composition to the site of interest, that is, at leastone skin region. There may be a plurality of applicator brushes in akit. For example, in a 30 day supply kit, there can be 60 applicators,such that there is one applicator for each eye, per application, for 30days. Alternately, there can be 2, 10, 20, 30, 40, 50, 60, 90, 120, etc.applicators per kit. Within the kit, the applicator brushes may bepackaged individually, or in sets of 2 or more. The applicator brushesare packaged such that they remain sterile until use. In certainembodiments, the applicator brushes can be packaged in plastic sheaths.Further, to prevent contamination of the eye, they are preferablysingle-use, disposable applicators.

The kit can also comprise a set of instructions. The instructions mayinclude information useful to the end user such as how to use thedelivery system and hair growth enhancing composition, how often to useit, etc.

The contents of the kit, the applicator brushes, container ofcomposition, and instructions, are enclosed in an outer casing. Theouter casing can be a box, a sealed bag, a foil pouch, etc. In certainembodiments, the delivery system, container and instructions areenclosed in a box. In other embodiments of the kit, the container andinstructions are contained in a first box, the delivery system iscontained in a second box, and the first and second box are containedtogether in a third box.

Aspects of the present specification disclose, in part, a method fortreating hair loss. Such method involves administering an effectiveamount of one or more AREs or pharmaceutical composition disclosedherein to at least one hair region or a portion thereof associated withhair loss, wherein the administration results in a reduction in theattribute associated with hair loss. The term “hair loss” is synonymouswith “alopecia” and refers to the absence or loss of hair from a skinsurface, including, without limitation, hair loss from the scalp, face,beard, head, pubic area, upper lip, eyebrows, and/or eyelids.

Aspects of the present specification disclose, in part, a method fortreating hair thinning. Such method involves administering an effectiveamount of one or more AREs or pharmaceutical composition disclosedherein to at least one hair region or a portion thereof associated withhair thinning, wherein the administration results in a reduction in theattribute associated with hair thinning. The term “hair thinning” refersto an age-related condition where hair follicles produce hairs that areshorter in length, smaller in diameter, lighter in color, and morefragile as opposed to no hair production at all. Hair thinning is acondition where the shaft of each hair becomes shorter in length,smaller in diameter (finer), less pigmented, and/or more fragile. Assuch, hair thinning is distinct from hair loss, a condition in which thehair follicle stops producing a hair shaft altogether. As discussedabove, the hair follicle is a complex mini organ. But like allbiological systems, the biologically active part of the hair follicleundergoes an aging process. This aging process is characterized by 1)the migration of the base of the hair follicle upwards toward the skinsurface, a decline in the synthesis of hair keratins, and a loss ofpigmentation. Although producing hairs, older hair follicles make hairsthat are shorter in length, smaller in diameter, lighter in color, andmore fragile. Taken together, this age-related shift in haircharacteristics manifests itself as hair thinning. Thinning hair affectsan estimated 40 million men and 25 million women in the United States.The emotional impact from hair loss can lead to anxiety, stress,depression, and lower self-esteem.

Aspects of the present specification disclose, in part, a method fortreating hair color loss. Such method involves administering aneffective amount of one or more AREs or pharmaceutical compositiondisclosed herein to at least one hair region or a portion thereofassociated with hair color loss, wherein the administration results in areduction in the attribute associated with hair color loss. The term“hair color loss” refers to the reduction of pigmentation of the hairshaft.

Hair includes that of mammalian species, including both humans andanimals. In humans, hair includes hair of the scalp, face, beard, head,pubic area, upper lip, eyebrows, and eyelids. In animals, hair includeshair of the entire surface of the body. For example, for animals raisedfor their pelts, such as, e.g., a mink, a chinchilla, fox, or a beaver,the compounds can be applied over the entire surface of the body toimprove the overall fur for commercial reasons. The process can also beused for cosmetic reasons in animals, e.g., applied to the skin of dogsand cats having bald patches due to mange or other diseases causing adegree of hair appearance.

Aspects of the present specification disclose, in part, a method fortreating a condition associated with a degenerative hair follicledisorder. Such method involves administering an effective amount of oneor more AREs or pharmaceutical composition disclosed herein to at leastone hair region or a portion thereof associated with a degenerative hairfollicle disorder, wherein the administration results in a reduction inthe attribute associated with the degenerative hair follicle disorder. Adegenerative hair follicle disorder is a condition where the function orstructure of a hair follicle progressively deteriorates over time. Adegenerative hair follicle disorder results in hair loss, hair thinning,and/or hair color loss. For example, a degenerative hair follicledisorder include alopecia including scarring alopecias and non-scarringalopecias.

In an aspect of this embodiment, a composition disclosed herein isadministered to an individual to treat a degenerative hair follicledisorder associated with hair loss, hair thinning, hair color loss, nonew hair shaft growth, reduced rate of hair shaft growth, reduced hairshaft diameter (thickness), reduced hair shaft length, reduced hairdensity, reduced keratinization of the hair shaft, increased fragility,reduced hair pigmentation, reduced hair shaft luster, reduced hairhealth, reduced time a hair follicle spends in anagen phase, reducedtime a hair follicle spends in catagen phase, reduced time a hairfollicle spends in telogen phase, premature release of hair shaft fromhair follicle, premature initiation of apoptosis in hair follicle,premature conversion of a terminal hair into a vellus hair.

Alopecia can be caused by a multitude of factors including, withoutlimitation, genetic make-up, functional disorder, hereditary disorder,hereditary disposition of the hair shaft or genodermatoses, chemicalbreakage such as over processing, or frequent use of chemical relaxer,heat damage as from repeated hot comb use, chronic exposure to tractionon hair shaft, compulsive hair pulling, telogen effluvium resulting fromphysical or psychological stress, secondary syphilis can cause “motheaten hair loss”, discoid lupus erythematosus or chronic cutanous lupuserythematosus, lichenplanopilaris, pseudopelade of Brocq, tuftedfolliculitis, dissecting cellulitis, alopecia mucinosa, keratosisfollicularis spinulosa decalvans, adverse effect from certain drugs suchas chemotherapy, radiation therapy, and testosterone booster tablets.Alopecia frequently occurs in patients undergoing treatment for canceror suffering from other diseases, such as AIDS, where cell-killing, orcytotoxic, drugs are used.

Alopecia is typically categorized as scarring or nonscarring. Scarringalopecia, also known as “alopecia cicatrisata” or “cicatricialalopecia,” refers to hair loss characterized by potentially permanentand irreversible destruction of hair follicles and their replacementwith scar tissue. Non-limiting examples of scarring alopecia includebullous diseases, chemical alopecia, discoid lupus erythematosus,severre folliculitis, lichen planopilaris, dissecting cellulitis,central centrifugal cicatricial alopecia, postmenopausal frontalfibrosing alopecia, and tumors and skin outgrowths, such as, e.g.,sebaceous nevus, basal cell carcinoma, and squamous cell carcinoma.

Nonscarring alopecia refers to hair loss without permanent destructionof the hair follicle. Non-limiting examples of nonscarring alopeciainclude anagen effluvium, alopecia adnata, alopecia androgenetica,alopecian AREata, alopecia congenitalis, alopecia diffusa, alopeciadisseminate, alopecia follicularis, alopecia leprotica, alopeciamarginalis, alopecia medicamentosa, alopecia mucinosa, alopecianeurotica, alopecia pityrodes, alopecia presenili, alopecia senilis,alopecia symptomatica, alopecia syphilitica, alopecia totalis, alopeciatoxica, alopecia triangularis, alopecia triangularis congenitalis,alopecia universalis, folliculitis, olliculitis decalvans, tractionalopecia, trichotillomania, telogen effluvium, and inherited disordersof the hair shaft.

In an embodiment, a pharmaceutical composition disclosed herein isadministered to an individual to treat a degenerative hair follicledisorder associated with scarring alopecia. In aspects of thisembodiment, a composition disclosed herein is administered to anindividual to treat a degenerative hair follicle disorder associatedwith a bullous disease, a chemical exposure, a discoid lupuserythematosus, a severre folliculitis, a lichen planopilaris, adissecting cellulitis, a central centrifugal cicatricial alopecia, apostmenopausal frontal fibrosing alopecia, a tumor, or a skin outgrowth.

In another embodiment, a pharmaceutical composition disclosed herein isadministered to an individual to treat a non-scarring alopecia. Inaspects of this embodiment, a composition disclosed herein isadministered to an individual to treat a degenerative hair follicledisorder associated anagen effluvium, alopecia adnata, alopeciaandrogenetica, alopecian AREata, alopecia congenitalis, alopeciadiffusa, alopecia disseminate, alopecia follicularis, alopecialeprotica, alopecia marginalis, alopecia medicamentosa, alopeciamucinosa, alopecia neurotica, alopecia pityrodes, alopecia presenili,alopecia senilis, alopecia symptomatica, alopecia syphilitica, alopeciatotalis, alopecia toxica, alopecia triangularis, alopecia triangulariscongenitalis, alopecia universalis, folliculitis, olliculitis decalvans,traction alopecia, trichotillomania, telogen effluvium, or inheriteddisorder of the hair shaft.

In another aspect of this embodiment, a degenerative hair follicledisorder associated with hair loss in an individual is treated byreducing an attribute associated with hair loss. In aspects of thisembodiment, reduction of the attribute associated with hair loss isaccomplished by increasing the rate of hair growth, increasing hairthickness, increasing hair length, increasing hair density, increasingnumber of hairs produce per follicle, increasing hair pigmentation,increasing hair luster, converting intermediate or vellus hair toterminal hair, increasing hair health, increasing the time a hairfollicle remains in anagen phase, increasing the time a hair follicleremains in catagen phase, increasing the time a hair follicle remains intelogen phase, prolonging or preventing the release of the hair shaftfrom the hair follicle, or prolonging or preventing the initiation ofapoptosis in a hair follicle.

In aspects of this embodiment, reduction of the attribute associatedwith a degenerative hair follicle disorder associated with hair thinningis accomplished by increasing the rate of hair growth, increasing hairthickness, increasing hair length, increasing hair density, increasingnumber of hairs produce per follicle, increasing keratin production inthe hair shaft, increasing hair shaft pigmentation, increasing hairshaft luster, converting intermediate or vellus hair to terminal hair,increasing hair health, increasing the time a hair follicle remains inanagen phase, increasing the time a hair follicle remains in catagenphase, or increasing the time a hair follicle remains in telogen phase.

In an embodiment, a pharmaceutical composition disclosed herein isadministered to an individual to treat a degenerative hair follicledisorder associated with hair color loss. In another aspect of thisembodiment, a composition disclosed herein is administered to anindividual to treat a degenerative hair follicle disorder associatedwith decreases pigmentation of the hair shaft, decreased melaninproduction, increased death of melanocytes associated with apoptosis orany other cause.

In aspects of this embodiment, reduction of the attribute associatedwith a degenerative hair follicle disorder associated with hair colorloss is accomplished by increasing pigmentation of the hair shaft,increasing melanin production, increasing hair luster, convertingintermediate or vellus hair to terminal hair, increasing hair health,increasing the time a hair follicle remains in anagen phase, increasingthe time a hair follicle remains in catagen phase, increasing the time ahair follicle remains in telogen phase, prolonging or preventingmelanocyte death, or prolonging or preventing the initiation ofapoptosis in a hair follicle.

Aspects of the present specification disclose, in part, a method ofimproving hair appearance. Such methods involve administering aneffective amount of one or more AREs or pharmaceutical compositiondisclosed herein to at least one hair region or a portion thereof,wherein administration improves an attribute of hair appearance. Thisadministration results in an improvement of at least one hair attributeincluding, without limitation, increased hair length, increased hairthickness, increased new hair growth, increased hair growth rate,increased hair number, increased conversion of intermediate hair intoterminal hair, increased hair density, increased number of hairs perfollicle, and/or increased hair color or darkness.

Aspects of the present specification disclose, in part, a method fortreating a skin condition, disease or disorder. Such method involvesadministering an effective amount of an ARE or pharmaceuticalcomposition disclosed herein to at least one skin region or a portionthereof associated with a skin condition, disease or disorder. As usedherein, the term “skin region” is synonymous with “epidermal region.” Inaspects of this embodiment, a skin condition, disease or disorderincludes, without limitation, an acne, an excessive sebum production, apost-wound scar formation, or a dermatological issue associated withpolycystic ovary disease.

An effective amount (or therapeutically effective amount) of the atleast one ARE disclosed herein is one that reduces or inhibits one ormore physiological conditions, attributes or symptoms of a skin or haircondition, disorder or disease associated with AR-mediated signaling. Aneffective amount may be determined by one of ordinary skill in the artbut will vary depending on the ARE employed, frequency of theapplication, and desired result.

In aspects of this embodiment, a therapeutically effective amount of theat least one ARE disclosed herein reduces or inhibits one or morephysiological conditions, attributes or symptoms of a skin or haircondition, disorder or disease associated with AR-mediated signaling by,e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least50%, at least 60%, at least 70%, at least 80%, at least 90% or at least95%. In yet other aspects of this embodiment, a therapeuticallyeffective amount of the at least one compound enhances an attributeassociated with hair by, e.g., about 10% to about 100%, about 10% toabout 90%, about 10% to about 80%, about 10% to about 70%, about 10% toabout 60%, about 10% to about 50%, about 10% to about 40%, about 20% toabout 100%, about 20% to about 90%, about 20% to about 80%, about 20% toabout 20%, about 20% to about 60%, about 20% to about 50%, about 20% toabout 40%, about 30% to about 100%, about 30% to about 90%, about 30% toabout 80%, about 30% to about 70%, about 30% to about 60%, or about 30%to about 50%. In aspects of this embodiment, a therapeutically effectivedose is the dosage sufficient to achieve the desired therapeutic effectfor, e.g., at least one day, at least two days, at least three days, atleast four days, at least five days, at least six days, at least sevendays, at least one week, at least two weeks, at least three weeks, atleast four weeks, at least one month, at least two months, at leastthree months, at least four months, at least five months, at least sixmonths, at least seven months, at least eight months, at least ninemonths, at least ten months, at least eleven months, or at least twelvemonths.

In aspects of this embodiment, an effective amount of an ARE disclosedherein generally is in the range of about 0.001 mg/kg/day to about 100mg/kg/day. In aspects of this embodiment, an effective amount of an AREdisclosed herein may be, e.g., at least 0.001 mg/kg/day, at least 0.01mg/kg/day, at least 0.1 mg/kg/day, at least 1.0 mg/kg/day, at least 5.0mg/kg/day, at least 10 mg/kg/day, at least 15 mg/kg/day, at least 20mg/kg/day, at least 25 mg/kg/day, at least 30 mg/kg/day, at least 35mg/kg/day, at least 40 mg/kg/day, at least 45 mg/kg/day, or at least 50mg/kg/day. In other aspects of this embodiment, an effective amount ofan ARE disclosed herein may be, e.g., at most 0.001 mg/kg/day, at most0.01 mg/kg/day, at most 0.1 mg/kg/day, at most 1.0 mg/kg/day, at most5.0 mg/kg/day, at most 10 mg/kg/day, at most 15 mg/kg/day, at most 20mg/kg/day, at most 25 mg/kg/day, at most 30 mg/kg/day, at most 35mg/kg/day, at most 40 mg/kg/day, at most 45 mg/kg/day, or at most 50mg/kg/day.

In other aspects of this embodiment, an effective amount of an AREdisclosed herein may be in the range of, e.g., about 0.001 mg/kg/day toabout 10 mg/kg/day, about 0.001 mg/kg/day to about 15 mg/kg/day, about0.001 mg/kg/day to about 20 mg/kg/day, about 0.001 mg/kg/day to about 25mg/kg/day, about 0.001 mg/kg/day to about 30 mg/kg/day, about 0.001mg/kg/day to about 35 mg/kg/day, about 0.001 mg/kg/day to about 40mg/kg/day, about 0.001 mg/kg/day to about 45 mg/kg/day, about 0.001mg/kg/day to about 50 mg/kg/day, about 0.001 mg/kg/day to about 75mg/kg/day, or about 0.001 mg/kg/day to about 100 mg/kg/day. In yet otheraspects of this embodiment, an effective amount of an ARE disclosedherein may be in the range of, e.g., about 0.01 mg/kg/day to about 10mg/kg/day, about 0.01 mg/kg/day to about 15 mg/kg/day, about 0.01mg/kg/day to about 20 mg/kg/day, about 0.01 mg/kg/day to about 25mg/kg/day, about 0.01 mg/kg/day to about 30 mg/kg/day, about 0.01mg/kg/day to about 35 mg/kg/day, about 0.01 mg/kg/day to about 40mg/kg/day, about 0.01 mg/kg/day to about 45 mg/kg/day, about 0.01mg/kg/day to about 50 mg/kg/day, about 0.01 mg/kg/day to about 75mg/kg/day, or about 0.01 mg/kg/day to about 100 mg/kg/day. In stillother aspects of this embodiment, an effective amount of an AREdisclosed herein may be in the range of, e.g., about 0.1 mg/kg/day toabout 10 mg/kg/day, about 0.1 mg/kg/day to about 15 mg/kg/day, about 0.1mg/kg/day to about 20 mg/kg/day, about 0.1 mg/kg/day to about 25mg/kg/day, about 0.1 mg/kg/day to about 30 mg/kg/day, about 0.1mg/kg/day to about 35 mg/kg/day, about 0.1 mg/kg/day to about 40mg/kg/day, about 0.1 mg/kg/day to about 45 mg/kg/day, about 0.1mg/kg/day to about 50 mg/kg/day, about 0.1 mg/kg/day to about 75mg/kg/day, or about 0.1 mg/kg/day to about 100 mg/kg/day.

In other aspects of this embodiment, an effective amount of an AREdisclosed herein may be in the range of, e.g., about 1 mg/kg/day toabout 10 mg/kg/day, about 1 mg/kg/day to about 15 mg/kg/day, about 1mg/kg/day to about 20 mg/kg/day, about 1 mg/kg/day to about 25mg/kg/day, about 1 mg/kg/day to about 30 mg/kg/day, about 1 mg/kg/day toabout 35 mg/kg/day, about 1 mg/kg/day to about 40 mg/kg/day, about 1mg/kg/day to about 45 mg/kg/day, about 1 mg/kg/day to about 50mg/kg/day, about 1 mg/kg/day to about 75 mg/kg/day, or about 1 mg/kg/dayto about 100 mg/kg/day. In yet other aspects of this embodiment, aneffective amount of an ARE disclosed herein may be in the range of,e.g., about 5 mg/kg/day to about 10 mg/kg/day, about 5 mg/kg/day toabout 15 mg/kg/day, about 5 mg/kg/day to about 20 mg/kg/day, about 5mg/kg/day to about 25 mg/kg/day, about 5 mg/kg/day to about 30mg/kg/day, about 5 mg/kg/day to about 35 mg/kg/day, about 5 mg/kg/day toabout 40 mg/kg/day, about 5 mg/kg/day to about 45 mg/kg/day, about 5mg/kg/day to about 50 mg/kg/day, about 5 mg/kg/day to about 75mg/kg/day, or about 5 mg/kg/day to about 100 mg/kg/day.

In other aspects of this embodiment, an effective amount of an AREdisclosed herein generally is in the range of about 0.001 mg/day toabout 100 mg/day. In aspects of this embodiment, an effective amount ofan ARE disclosed herein may be, e.g., at least 0.001 mg/day, at least0.01 mg/day, at least 0.1 mg/day, at least 1.0 mg/day, at least 5.0mg/day, at least 10 mg/day, at least 15 mg/day, at least 20 mg/day, atleast 25 mg/day, at least 30 mg/day, at least 35 mg/day, at least 40mg/day, at least 45 mg/day, or at least 50 mg/day. In other aspects ofthis embodiment, an effective amount of an ARE disclosed herein may be,e.g., at most 0.001 mg/day, at most 0.01 mg/day, at most 0.1 mg/day, atmost 1.0 mg/day, at most 5.0 mg/day, at most 10 mg/day, at most 15mg/day, at most 20 mg/day, at most 25 mg/day, at most 30 mg/day, at most35 mg/day, at most 40 mg/day, at most 45 mg/day, or at most 50 mg/day.

In other aspects of this embodiment, an effective amount of an AREdisclosed herein may be in the range of, e.g., about 0.001 mg/day toabout 10 mg/day, about 0.001 mg/day to about 15 mg/day, about 0.001mg/day to about 20 mg/day, about 0.001 mg/day to about 25 mg/day, about0.001 mg/day to about 30 mg/day, about 0.001 mg/day to about 35 mg/day,about 0.001 mg/day to about 40 mg/day, about 0.001 mg/day to about 45mg/day, about 0.001 mg/day to about 50 mg/day, about 0.001 mg/day toabout 75 mg/day, or about 0.001 mg/day to about 100 mg/day. In yet otheraspects of this embodiment, an effective amount of an ARE disclosedherein may be in the range of, e.g., about 0.01 mg/day to about 10mg/day, about 0.01 mg/day to about 15 mg/day, about 0.01 mg/day to about20 mg/day, about 0.01 mg/day to about 25 mg/day, about 0.01 mg/day toabout 30 mg/day, about 0.01 mg/day to about 35 mg/day, about 0.01 mg/dayto about 40 mg/day, about 0.01 mg/day to about 45 mg/day, about 0.01mg/day to about 50 mg/day, about 0.01 mg/day to about 75 mg/day, orabout 0.01 mg/day to about 100 mg/day. In still other aspects of thisembodiment, an effective amount of an ARE disclosed herein may be in therange of, e.g., about 0.1 mg/day to about 10 mg/day, about 0.1 mg/day toabout 15 mg/day, about 0.1 mg/day to about 20 mg/day, about 0.1 mg/dayto about 25 mg/day, about 0.1 mg/day to about 30 mg/day, about 0.1mg/day to about 35 mg/day, about 0.1 mg/day to about 40 mg/day, about0.1 mg/day to about 45 mg/day, about 0.1 mg/day to about 50 mg/day,about 0.1 mg/day to about 75 mg/day, or about 0.1 mg/day to about 100mg/day.

In other aspects of this embodiment, an effective amount of an AREdisclosed herein may be in the range of, e.g., about 1 mg/day to about10 mg/day, about 1 mg/day to about 15 mg/day, about 1 mg/day to about 20mg/day, about 1 mg/day to about 25 mg/day, about 1 mg/day to about 30mg/day, about 1 mg/day to about 35 mg/day, about 1 mg/day to about 40mg/day, about 1 mg/day to about 45 mg/day, about 1 mg/day to about 50mg/day, about 1 mg/day to about 75 mg/day, or about 1 mg/day to about100 mg/day. In yet other aspects of this embodiment, an effective amountof an ARE disclosed herein may be in the range of, e.g., about 5 mg/dayto about 10 mg/day, about 5 mg/day to about 15 mg/day, about 5 mg/day toabout 20 mg/day, about 5 mg/day to about 25 mg/day, about 5 mg/day toabout 30 mg/day, about 5 mg/day to about 35 mg/day, about 5 mg/day toabout 40 mg/day, about 5 mg/day to about 45 mg/day, about 5 mg/day toabout 50 mg/day, about 5 mg/day to about 75 mg/day, or about 5 mg/day toabout 100 mg/day.

Dosing can be single dosage or cumulative (serial dosing), and can bereadily determined by one skilled in the art. For instance, method oftreatment disclosed herein may comprise a one-time administration of aneffective amount of an ARE or pharmaceutical composition disclosedherein. As a non-limiting example, an effective amount of an ARE orpharmaceutical composition disclosed herein can be administered once toan individual, e.g., as a single injection or deposition. Alternatively,a method of treatment disclosed herein may comprise multipleadministrations of an effective amount of an ARE or pharmaceuticalcomposition disclosed herein carried out over a range of time periods,such as, e.g., daily, every other day, every third of day, once a week,multiple times per week, once a month, multiple times per month, once ayear or multiple times per year. A pharmaceutical composition disclosedherein can be administered multiple times per day, e.g., twice a day,three times a day, four time a day, five times a day, or six times aday. The timing of administration can vary from individual toindividual, depending upon such factors as the severity of anindividual's symptoms. For example, an effective amount of an ARE orpharmaceutical composition disclosed herein can be administered to anindividual 1 to 5 times every day for an indefinite period of time, oruntil the individual no longer requires therapy, e.g., for a period oftreatment of at least one week, more preferably at least one month, morepreferably at least three months, and most preferably at least sixmonths. A person of ordinary skill in the art will recognize that thecondition of the individual can be monitored throughout the course oftreatment and that the effective amount of a pharmaceutical disclosedherein that is administered can be adjusted accordingly.

In aspects of this embodiment, hair length from a treated regionincreases relative to an untreated region by, e.g., at least 5%, atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 40%, at least 50%, at least 60%, at least 70%, at least 80%, atleast 90%, or at least 95%. In yet other aspects of this embodiment,hair length increases relative to an untreated region by, e.g., about 5%to about 100%, about 15% to about 100%, about 25% to about 100%, about35% to about 100%, or about 45% to about 100%. In still other aspects ofthis embodiment, hair length from a treated region increases relative toan untreated region by, e.g., about 1 mm to about 500 mm, about 10 mm toabout 500 mm, or about 100 mm to about 500 mm. Is further aspects ofthis embodiment, hair length from a treated region increases relative toan untreated region by, e.g., at least 1 mm, at least, 2 mm, at least, 3mm, at least 4 mm, at least 5 mm, at least 6 mm, at least 7 mm, at least8 mm, at least 9 mm, or at least 10 mm.

In other aspects embodiment, hair thickness from a treated regionincreases relative to an untreated region by, e.g., at least 5%, atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 40%, at least 50%, at least 60%, at least 70%, at least 80%, atleast 90%, or at least 95%. In yet other aspects of this embodiment,hair thickness from a treated region increases relative to an untreatedregion by, e.g., about 5% to about 100%, about 15% to about 100%, about25% to about 100%, about 35% to about 100%, or about 45% to about 100%.In still other aspects of this embodiment, hair thickness from a treatedregion increases relative to an untreated region by, e.g., about 1 μm²to about 1 mm², about 10 μm² to about 1 mm², about 100 μm² to about 1mm², or about 100 μm² to about 2 mm². Is further aspects of thisembodiment, hair thickness from a treated region increases relative toan untreated by, e.g., at least 100 μm², at least 200 μm², at least 300μm², at least 400 μm², at least 500 μm², at least 600 μm², at least 700μm², at least 800 μm², at least 900 μm², at least 1 mm², at least 2 mm²,or at least 3 mm².

In aspects of this embodiment, new hair growth from a treated regionincreases relative to an untreated region by, e.g., at least 5%, atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 40%, at least 50%, at least 60%, at least 70%, at least 80%, atleast 90%, or at least 95%. In other aspects of this embodiment, newhair growth from a treated region increases relative to an untreatedregion by, e.g., about 5% to about 100%, about 15% to about 100%, about25% to about 100%, about 35% to about 100%, or about 45% to about 100%.

In other aspects of this embodiment, the rate of hair growth from atreated region increases relative to an untreated region by, e.g., atleast 5%, at least 10%, at least 15%, at least 20%, at least 25%, atleast 30%, at least 40%, at least 50%, at least 60%, at least 70%, atleast 80%, at least 90%, or at least 95%. In yet other aspects of thisembodiment, the rate of hair growth from a treated region increasesrelative to an untreated region by, e.g., about 5% to about 100%, about15% to about 100%, about 25% to about 100%, about 35% to about 100%, orabout 45% to about 100%.

In other aspects embodiment, the hair numbers from a treated regionincreases relative to an untreated region by, e.g., at least 5%, atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 40%, at least 50%, at least 60%, at least 70%, at least 80%, atleast 90%, or at least 95%. In yet other aspects of this embodiment,hair numbers from a treated region increases relative to an untreatedregion by, e.g., about 5% to about 100%, about 15% to about 100%, about25% to about 100%, about 35% to about 100%, or about 45% to about 100%.

In other aspects embodiment, the conversion of intermediate hairs intoterminal hairs from a treated region increases relative to an untreatedregion by, e.g., at least 5%, at least 10%, at least 15%, at least 20%,at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, atleast 70%, at least 80%, at least 90%, or at least 95%. In yet otheraspects of this embodiment, the conversion of intermediate hairs intoterminal hairs from a treated region increases relative to an untreatedregion by, e.g., about 5% to about 100%, about 15% to about 100%, about25% to about 100%, about 35% to about 100%, or about 45% to about 100%.

In other aspects embodiment, hair density from a treated regionincreases relative to an untreated region by, e.g., at least 5%, atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 40%, at least 50%, at least 60%, at least 70%, at least 80%, atleast 90%, or at least 95%. In yet other aspects of this embodiment,hair density from a treated region increases relative to an untreatedregion by, e.g., about 5% to about 100%, about 15% to about 100%, about25% to about 100%, about 35% to about 100%, or about 45% to about 100%.

In other aspects embodiment, the number of hairs produce per hairfollicle from a treated region increases relative to an untreated regionby, e.g., at least 5%, at least 10%, at least 15%, at least 20%, atleast 25%, at least 30%, at least 40%, at least 50%, at least 60%, atleast 70%, at least 80%, at least 90%, or at least 95%. In yet otheraspects of this embodiment, the number of hairs produce per hairfollicle from a treated region increases relative to an untreated regionby, e.g., about 5% to about 100%, about 15% to about 100%, about 25% toabout 100%, about 35% to about 100%, or about 45% to about 100%. Instill other aspects of this embodiment, the number of hairs produce perhair follicle from a treated region increases relative to an untreatedregion by, e.g., 2 or more hair shafts/follicle, 3 or more hairshafts/follicle, 4 or more hair shafts/follicle, or 5 or more hairshafts/follicle. In further aspects of this embodiment, the number ofhairs produced per hair follicle from a treated region increasesrelative to an untreated region by, e.g., 2 hair shafts/follicle, 3 hairshafts/follicle, 4 hair shafts/follicle, or 5 hair shafts/follicle. Inyet further aspects of this embodiment, the number of hairs produce perhair follicle from a treated region increases relative to an untreatedregion by, e.g., 2 to 5 hair shafts/follicle, 3 to 5 hairshafts/follicle, 2 to 4 hair shafts/follicle, or 2 to 3 hairshafts/follicle.

In other aspects embodiment, hair color from a treated region increasesrelative to an untreated region by, e.g., at least 5%, at least 10%, atleast 15%, at least 20%, at least 25%, at least 30%, at least 40%, atleast 50%, at least 60%, at least 70%, at least 80%, at least 90%, or atleast 95%. In other aspects of this embodiment, hair color from atreated region increases relative to an untreated region by, e.g., about5% to about 100%, about 15% to about 100%, about 25% to about 100%,about 35% to about 100%, or about 45% to about 100%.

In other aspects embodiment, hair pigmentation and/or melanization froma treated region increases relative to an untreated region by, e.g., atleast 5%, at least 10%, at least 15%, at least 20%, at least 25%, atleast 30%, at least 40%, at least 50%, at least 60%, at least 70%, atleast 80%, at least 90%, or at least 95%. In other aspects of thisembodiment, hair pigmentation and/or melanization from a treated regionincreases relative to an untreated region by, e.g., about 5% to about100%, about 15% to about 100%, about 25% to about 100%, about 35% toabout 100%, or about 45% to about 100%.

A pharmaceutical composition disclosed herein can be applied accordingto a method disclosed herein to a site of skin and/or thinning hair orbaldness. Application of a compositions disclosed herein can be byrubbing, pouring, sprinkling, or spraying on, or otherwise applied to asite of skin and/or thinning hair or baldness. A pharmaceuticalcomposition disclosed herein can be applied by introducing orimpregnating a composition into or onto a solid support such as, e.g., adressing, a wipe, a towelette, a towel, a mitt, a glove, or a mask andthen applying the composition to a site of skin and/or thinning hair orbaldness. A pharmaceutical composition disclosed herein can be appliedby using a delivery device, such as, e.g., an aerosol dispenser, a pumpspray, a trigger spray or a squeeze bottle, to apply a composition to asite of skin and/or thinning hair or baldness.

Aspects of the present invention can also be described as follows:

-   1. A compound of formula I disclosed herein, wherein ARA is an AR    antagonist, L is a linker molecule and EE is an AR elimination    promoter or elimination enhancer element.-   2. The compound of embodiment 1, wherein the AR antagonist includes    apalutamide, bicalutamide, canrenone, chlormadinone acetate,    cimetidine, Compound ARA 1, cyproterone acetate, drospirenone,    enzalutamide, flutamide, ketoconazole, megestrol acetate,    methoxybenzyl lactam, nilutamide, RU58841, spironolactone,    ortopilutamide (fluridil).-   3. The compound of embodiment 1 or 2, wherein the linker molecule is    formula II disclosed herein, wherein R¹ and R² are each    independently H, OH, COOH, NH₂, R³OH, R³COOH, OR³OH, OR³COOH,    R³NH(CO)R⁴, R³NH(CO)R⁴OH, R³NH(CO)R⁴COOH; R³ and R⁴ are each    independently C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, or C₂₋₁₀ alkynyl; and n    any integer from 0 to 10.-   4. The compound of embodiment 3, wherein R¹ and R² are each    independently H, OH, COOH, NH₂, R³OH, R³COOH, OR³OH, OR³COOH,    R³NH(CO)R⁴, R³NH(CO)R⁴OH, or R³NH(CO)R⁴COOH; R³ and R⁴ are each    independently C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; and n any    integer from 0 to 10.-   5. The compound of embodiment 4, wherein R¹ and R² are each    independently H, OH, COOH, NH₂, R³OH, R³COOH, OR³OH, OR³COOH,    R³NH(CO)R⁴, R³NH(CO)R⁴OH, or R³NH(CO)R⁴COOH; R³ and R⁴ are each    independently C₁₋₄ alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl; and n any    integer from 0 to 5.-   6. The compound of embodiment 3, wherein R¹ and R² are each    independently H, OH, COOH, NH₂, R³OH, R³COOH, OR³OH, OR³COOH, or    R³NH(CO)R⁴OH; R³ and R⁴ are each independently C₁₋₁₀ alkyl; and n    any integer from 0 to 10.-   7. The compound of embodiment 6, wherein R¹ and R² are each    independently H, OH, COOH, NH₂, R³OH, R³COOH, OR³OH, OR³COOH, or    R³NH(CO)R⁴OH; R³ and R⁴ are each independently C₁₋₆ alkyl; and n any    integer from 0 to 10.-   8. The compound of embodiment 7, wherein R¹ and R² are each    independently H, OH, COOH, NH₂, R³OH, R³COOH, OR³OH, OR³COOH, or    R³NH(CO)R⁴OH; R³ and R⁴ are each independently C₁₋₆ alkyl; and n any    integer from 0 to 5.-   9. The compound of embodiment 3, wherein R¹ is OH, COOH, NH₂, R³OH,    R³COOH, or R³NH(CO)R⁴OH; R² is OH, COOH, NH₂, R³COOH, or OR³COOH, R³    and R⁴ are each independently C₁₋₁₀ alkyl; and n any integer from 0    to 10.-   10. The compound of embodiment 9, wherein R¹ is OH, COOH, NH₂, R³OH,    R³COOH, or R³NH(CO)R⁴OH; R² is OH, COOH, NH₂, R³COOH, or OR³COOH, R³    and R⁴ are each independently C₁₋₆ alkyl; and n any integer from 0    to 10.-   11. The compound of embodiment 10, wherein R¹ is OH, COOH, NH₂,    R³OH, R³COOH, or R³NH(CO)R⁴OH; R² is OH, COOH, NH₂, R³COOH, or    OR³COOH, R³ and R⁴ are each independently C₁₋₆ alkyl; and n any    integer from 0 to 5.-   12. The compound of embodiment 11, wherein R¹ is OH, R³OH, R³COOH,    or R³NH(CO)R⁴OH; R² is OH, COOH, NH₂, R³COOH, or OR³COOH, R³ and R⁴    are each independently C₁₋₆ alkyl; and n any integer from 0 to 5.-   13. The compound of embodiment 12, wherein R¹ is OH, R³OH, R³COOH,    or R³NH(CO)R⁴OH; R² is OH, COOH, NH₂, R³COOH, or OR³COOH, R³ and R⁴    are each independently C₁₋₄ alkyl; and n any integer from 0 to 4.-   14. The compound of embodiment 13, wherein R¹ is OH, C—C—OH, C—COOH,    or C—C—NH—CO—C—C—C—OH; R² is OH, COOH, NH₂, C—COOH, or O—C—COOH; and    n any integer from 0 to 10.-   15. The compound of embodiment 14, wherein R¹ is OH, C—C—OH, C—COOH,    or C—C—NH—CO—C—C—C—OH; R² is OH, COOH, NH₂, C—COOH, or O—C—COOH; and    n any integer from 0 to 8.-   16. The compound of embodiment 15, wherein R¹ is OH, C—C—OH, C—COOH,    or C—C—NH—CO—C—C—C—OH; R² is OH, COOH, NH₂, C—COOH, or O—C—COOH; and    n any integer from 0 to 6.-   17. The compound of embodiment 16, wherein R¹ is OH, C—C—OH, C—COOH,    or C—C—NH—CO—C—C—C—OH; R² is OH, COOH, NH₂, C—COOH, or O—C—COOH; and    n any integer from 0 to 4.-   18. The compound of any one of embodiments 1-3, wherein the linker    molecule is formula III disclosed herein, wherein n any integer from    0 to 10.-   19. The compound of embodiment 18, wherein n any integer from 0 to    8, or any integer from 0 to 6, or any integer from 0 to 4.-   20. The compound of any one of embodiments 1-3, 18 or 19, wherein    the linker molecule is

-   21. The compound of any one of embodiments 1-3, wherein the linker    molecule is formula IV disclosed herein, wherein n any integer from    0 to 10.-   22. The compound of embodiment 21, wherein n any integer from 0 to    8, or any integer from 0 to 6, or any integer from 0 to 4.-   23. The compound of any one of embodiments 1-3, 21 or 22, wherein    the linker molecule is

-   24. The compound of any one of embodiments 1-3, wherein the linker    molecule is formula V disclosed herein, wherein n any integer from 0    to 10.-   25. The compound of embodiment 24, wherein n any integer from 0 to    8, or any integer from 0 to 6, or any integer from 0 to 4.-   26. The compound of any one of embodiments 1-3, 24 or 25, wherein    the linker molecule is

-   27. The compound of any one of embodiments 1-3, wherein the linker    molecule is formula VI disclosed herein, wherein n any integer from    0 to 10.-   28. The compound of embodiment 27, wherein n any integer from 0 to    8, or any integer from 0 to 6, or any integer from 0 to 4.-   29. The compound of any one of embodiments 1-3, 27 or 28, wherein    the linker molecule is

-   30. The compound of any one of embodiments 1-3, wherein the linker    molecule is formula VII disclosed herein, wherein n any integer from    0 to 10.-   31. The compound of embodiment 30, wherein n any integer from 0 to    8, or any integer from 0 to 6, or any integer from 0 to 4.-   32. The compound of any one of embodiments 1-3, 30 or 31, wherein    the linker molecule is

-   33. The compound of any one of embodiments 1-3, wherein the linker    molecule is formula VIII disclosed herein, wherein n any integer    from 0 to 10.-   34. The compound of embodiment 33, wherein n any integer from 0 to    8, or any integer from 0 to 6, or any integer from 0 to 4.-   35. The compound of any one of embodiments 1-3, 33 or 34, wherein    the linker molecule is

-   36. The compound of any one of embodiments 1-3, wherein the linker    molecule is formula IX disclosed herein, wherein n any integer from    0 to 10.-   37. The compound of embodiment 36, wherein n any integer from 0 to    8, or any integer from 0 to 6, or any integer from 0 to 4.-   38. The compound of any one of embodiments 1-3, 36 or 37, wherein    the linker molecule is

-   39. The compound of any one of embodiments 1-3, wherein the linker    molecule is formula X disclosed herein, wherein n any integer from 0    to 10.-   40. The compound of embodiment 39, wherein n any integer from 0 to    8, or any integer from 0 to 6, or any integer from 0 to 4.-   41. The compound of any one of embodiments 1-3, 39 or 40 wherein the    linker molecule is

-   42. The compound of any one of embodiments 1-41, wherein the AR    eliminator promoter or enhancing element is a hydrophobic tag or an    E3 ligase-recruiting moiety.-   43. The compound of embodiment 42, wherein the hydrophobic tag is an    adamantane moiety.-   44. The compound of embodiment 43, wherein the adamantane moiety is    formula XI disclosed herein, wherein R⁵ is H, OH, COOH, NH₂, a    halogen, R⁶OH, R⁶COOH, R⁶C(O)NH₂, or R⁶C(O)R⁷; R⁶ is C₁₋₁₀ alkyl,    C₂₋₁₀ alkenyl, or C₂₋₁₀ alkynyl; and R⁷ is a halogen.-   45. The compound of embodiment 44, wherein R⁵ is H, OH, COOH, NH₂, a    halogen, R⁶OH, R⁶COOH, R⁶C(O)NH₂ or R⁶C(O)R⁷; R⁶ is C₁₋₆ alkyl, C₂₋₆    alkenyl, or C₂₋₆ alkynyl; and R⁷ is a halogen.-   46. The compound of embodiment 45, wherein R⁵ is H, OH, COOH, NH₂, a    halogen, R⁶OH, R⁶COOH, R⁶C(O)NH₂ or R⁶C(O)R⁷; R⁶ is C₁₋₄ alkyl, C₂₋₄    alkenyl, or C₂₋₄ alkynyl; and R⁷ is a halogen.-   47. The compound of any one of embodiments 44-46, wherein the    halogen is fluorine, chlorine, bromine, iodine, astatine or    ununseptium.-   48. The compound of any one of embodiments 44-47, wherein R⁵ is H,    OH, COOH, NH₂, F, Br, Cl, I, R⁶OH, R⁶COOH, R⁶C(O)NH₂ or R⁶C(O)R⁷; R⁶    is C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; and R⁷ is a F, Br, Cl    or I.-   49. The compound of any one of embodiments 44-48, wherein the    adamantine moiety is

-   50. The compound of embodiment 42, wherein the hydrophobic tag is a    Boc-protected amino acid.-   51. The compound of embodiment 50, wherein the Boc-protected amino    acid includes a glutamine, arginine, glutamic acid, phenylalanine,    aspartic acid, cysteine, lysine or aspartame.-   52. The compound of embodiment 50 or 51, wherein the Boc-protected    amino acid a tert-butyl carbamate-protected arginine (BOC₃Arg)    moiety, an iso-butyl carbamate-protected lysine (BOC₂Lys) moiety, an    iso-butyl carbamate-protected aspartic acid (BOC₂Asp) moiety, an    iso-butyl carbamate-protected asparagine (BOC₂Asn) moiety, an    iso-butyl carbamate-protected glutamic acid (BOC₂Glu) moiety, or an    iso-butyl carbamate-protected glutamine (BOC₂Gln) moiety.-   53. The compound of any one of embodiments 50-52, wherein the    Boc-protected amino acid is

-   54. The compound of embodiment 42, wherein the E3 ligase-recruiting    moiety is a hypoxia-inducible factor 1α (HIF-1α) moiety.-   55. The compound of embodiment 54, wherein the HIF-1α moiety is    formula XII disclosed herein, wherein R⁸ is H, OH, COOH, NH₂, a    halogen, R⁹OH, R⁹COOH, R⁹C(O)NH₂, or R⁹C(O)R¹⁰; R⁹ is C₁₋₁₀ alkyl,    C₂₋₁₀ alkenyl, or C₂₋₁₀ alkynyl; and R¹⁰ is a halogen.-   56. The compound of embodiment 55, wherein R⁸ is H, OH, COOH, NH₂, a    halogen, R⁹OH, R⁹COOH, R⁹C(O)NH₂, or R⁹C(O)R¹⁰; R⁹ is C₁₋₆ alkyl,    C₂₋₆ alkenyl, or C₂₋₆ alkynyl; and R¹⁰ is a halogen.-   57. The compound of embodiment 56, wherein R⁸ is H, OH, COOH, NH₂, a    halogen, R⁹OH, R⁹COOH, R⁹C(O)NH₂, or R⁹C(O)R¹⁰; R⁹ is C₁₋₄ alkyl,    C₂₋₄ alkenyl, or C₂₋₄ alkynyl; and R¹⁰ is a halogen.-   58. The compound of any one of embodiments 55-57, wherein the    halogen is fluorine, chlorine, bromine, iodine, astatine or    ununseptium.-   59. The compound of any one of embodiments 55-58, wherein R⁸ is H,    OH, COOH, NH₂, F, Br, Cl, I, R⁹OH, R⁹COOH, R⁹C(O)NH₂, or R⁹C(O)R¹⁰;    R⁹ is C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; and R¹⁰ is a F, Br,    Cl or I.-   60. The compound of any one of embodiments 55-59, wherein the HIF-1α    moiety is

-   61. The compound of embodiment 42, wherein the E3 ligase-recruiting    moiety is a Nutlin moiety.-   62. The compound of embodiment 61, wherein the Nutlin moiety is    formula XIII disclosed herein, wherein R¹¹ is H, OH, COOH, NH₂, a    halogen, R¹²OH, R¹²COOH, R¹²C(O)NH₂, or R¹²C(O)R¹³; R¹² is C₁₋₁₀    alkyl, C₂₋₁₀ alkenyl, or C₂₋₁₀ alkynyl; and R¹³ is a halogen.-   63. The compound of embodiment 62, wherein R¹¹ is H, OH, COOH, NH₂,    a halogen, R¹²OH, R¹²COOH, R¹²C(O)NH₂, or R¹²C(O)R¹³; R¹² is C₁₋₆    alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; and R¹³ is a halogen.-   64. The compound of embodiment 63, wherein R¹¹ is H, OH, COOH, NH₂,    a halogen, R¹²OH, R¹²COOH, R¹²C(O)NH₂, or R¹²C(O)R¹³; R¹² is C₁₋₄    alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl; and R¹³ is a halogen.-   65. The compound of any one of embodiments 62-64, wherein the    halogen is fluorine, chlorine, bromine, iodine, astatine or    ununseptium.-   66. The compound of any one of embodiments 62-65, wherein R¹¹ is H,    OH, COOH, NH₂, F, Br, Cl, I, R¹²OH, R¹²COOH, R¹²C(O)NH₂, or    R¹²C(O)R¹³; R¹² is C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; and    R¹³ is a F, Br, Cl or I.-   67. The compound of embodiment 42, wherein the E3 ligase-recruiting    moiety is a bestatin moiety.-   68. The compound of embodiment 61, wherein the bestatin moiety is    formula XIV disclosed herein, wherein R¹⁴ is H, OH, COOH, NH₂, a    halogen, R¹⁵OH, R¹⁵COOH, R¹⁵C(O)NH₂, or R¹⁵C(O)R¹⁶; R¹⁵ is C₁₋₁₀    alkyl, C₂₋₁₀ alkenyl, or C₂₋₁₀ alkynyl; and R¹⁶ is a halogen.-   69. The compound of embodiment 68, wherein R¹⁴ is H, OH, COOH, NH₂,    a halogen, R¹⁵OH, R¹⁵COOH, R¹⁵C(O)NH₂, or R¹⁵C(O)R¹⁶; R¹⁵ is C₁₋₆    alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; and R¹⁶ is a halogen.-   70. The compound of embodiment 69, wherein R¹⁴ is H, OH, COOH, NH₂,    a halogen, R¹⁵OH, R¹⁵COOH, R¹⁵C(O)NH₂, or R¹⁵C(O)R¹⁶; R¹⁵ is C₁₋₄    alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl; and R¹⁶ is a halogen.-   71. The compound of any one of embodiments 68-70, wherein the    halogen is fluorine, chlorine, bromine, iodine, astatine or    ununseptium.-   72. The compound of any one of embodiments 68-71, wherein R¹⁴ is H,    OH, COOH, NH₂, F, Br, Cl, I, R¹⁵OH, R¹⁵COOH, R¹⁵C(O)NH₂, or    R¹⁵C(O)R¹⁶; R¹⁵ is C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; and    R¹⁶ is a F, Br, Cl or I.-   73. The compound of embodiment 42, wherein the E3 ligase-recruiting    moiety is a phthalimide moiety.-   74. The compound of embodiment 61, wherein the phthalimide moiety is    formula XV disclosed herein, wherein R¹⁷ is H, OH, COOH, NH₂, a    halogen, R¹⁹OH, R¹⁹COOH, R¹⁹C(O)NH₂, or R¹⁹C(O)R²⁰, NHR¹⁹OH,    NHR¹⁹COOH, NHR¹⁹C(O)NH₂, or NHR¹⁹C(O)R²⁰; R¹⁸ is H, OH, O, COOH, or    C₁₋₆; R¹⁹ is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, or C₂₋₁₀ alkynyl; and R²⁰    is a halogen.-   75. The compound of embodiment 74, wherein R¹⁷ is H, OH, COOH, NH₂,    a halogen, R¹⁹OH, R¹⁹COOH, R¹⁹C(O)NH₂, or R¹⁹C(O)R²⁰, NHR¹⁹OH,    NHR¹⁹COOH, NHR¹⁹C(O)NH₂, or NHR¹⁹C(O)R²⁰; R¹⁸ is H, OH, O, COOH, or    C₁₋₆; R¹⁹ is C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; and R²⁰ is a    halogen.-   76. The compound of embodiment 75, wherein R¹⁷ is H, OH, COOH, NH₂,    a halogen, R¹⁹OH, R¹⁹COOH, R¹⁹C(O)NH₂, or R¹⁹C(O)R²⁰, NHR¹⁹OH,    NHR¹⁹COOH, NHR¹⁹C(O)NH₂, or NHR¹⁹C(O)R²⁰; R¹⁸ is H, OH, O, COOH, or    C₁₋₆; R¹⁹ is C₁₋₄ alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl; and R²⁰ is a    halogen.-   77. The compound of any one of embodiments 74-76, wherein the    halogen is fluorine, chlorine, bromine, iodine, astatine or    ununseptium.-   78. The compound of any one of embodiments 74-78, wherein R¹⁷ is H,    OH, COOH, NH₂, F, Br, Cl, I, R¹⁹OH, R¹⁹COOH, R¹⁹C(O)NH₂, or    R¹⁹C(O)R²⁰, NHR¹⁹OH, NHR¹⁹COOH, NHR¹⁹C(O)NH₂, or NHR¹⁹C(O)R²⁰; is H,    OH, O, COOH, or C₁₋₆; R¹⁹ is C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆    alkynyl; and R²⁰ is a F, Br, Cl or I.-   79. The compound of embodiment 73 or 74, wherein the phthalimide    moiety is any one of formulas XVI disclosed herein, XVII, XVIII or    XIX, wherein R²⁰ is H, OH, COOH, NH₂, a halogen, R²¹OH, R²¹COOH,    R²¹C(O)NH₂, or R²¹C(O)R²²; R²¹ is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, or    C₂₋₁₀ alkynyl; and R²² is a halogen.-   80. The compound of embodiment 79, wherein R²⁰ is H, OH, COOH, NH₂,    a halogen, R²¹OH, R²¹COOH, R²¹C(O)NH₂, or R²¹C(O)R²²; R²¹ is C₁₋₆    alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; and R²² is a halogen.-   81. The compound of embodiment 80, wherein R²⁰ is H, OH, COOH, NH₂,    a halogen, R²¹OH, R²¹COOH, R²¹C(O)NH₂, or R²¹C(O)R²²; and R²¹ is    C₁₋₄ alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl; and R²² is a halogen.-   82. The compound of any one of embodiments 79-81, wherein the    halogen is fluorine, chlorine, bromine, iodine, astatine or    ununseptium.-   83. The compound of any one of embodiments 79-82, wherein R²⁰ is H,    OH, COOH, NH₂, F, Br, Cl, I, R²¹OH, R²¹COOH, R²¹C(O)NH₂, or    R²¹C(O)R²²; and R²¹ is C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;    and R²² is a F, Br, Cl or I.-   84. The compound of any one of embodiments 1-83, wherein the    compound is of formula XX disclosed herein, wherein n any integer    from 0 to 10.-   85. The compound of embodiment 84, wherein n any integer from 0 to    8, or any integer from 0 to 6, or any integer from 0 to 4.-   86. The compound of embodiment 84 or 85, wherein the compound is    Compound 38 or Compound 39.-   87. The compound of any one of embodiments 1-83, wherein the    compound is Compound 37.-   88. The compound of any one of embodiments 1-83, wherein the    compound is of formula XXI disclosed herein, wherein n any integer    from 0 to 10.-   89. The compound of embodiment 88, wherein n any integer from 0 to    8, or any integer from 0 to 6, or any integer from 0 to 4.-   90. The compound of embodiment 88 or 89, wherein the compound is    Compound 41 or Compound 42.-   91. The compound of any one of embodiments 1-83, wherein the    compound is Compound 40.-   92. The compound of any one of embodiments 1-83, wherein the    compound is of formula XXII disclosed herein, wherein n any integer    from 0 to 10.-   93. The compound of embodiment 92, wherein n any integer from 0 to    8, or any integer from 0 to 6, or any integer from 0 to 4.-   94. The compound of embodiment 92 or 93, wherein the compound is    Compound 43, Compound 44, Compound 45, or Compound 46.-   95. The compound of any one of embodiments 1-83, wherein the    compound is of formula XXIII disclosed herein, wherein n any integer    from 0 to 10.-   96. The compound of embodiment 95, wherein n any integer from 0 to    8, or any integer from 0 to 6, or any integer from 0 to 4.-   97. The compound of embodiment 95 or 96, wherein the compound is    Compound 47, Compound 48, Compound 49, or Compound 50.-   98. The compound of any one of embodiments 1-83, wherein the    compound is Compound 51, Compound 52, Compound 53, or Compound 54.-   99. A pharmaceutical composition comprising one or more compounds    defined in any one of embodiments 1-98.-   100. The pharmaceutical composition of embodiment 99, wherein the    one or more compounds are in an amount of about 1 μg, about 2 μg,    about 3 μg, about 4 μg, about 5 μg, about 6 μg, about 7 μg, about 8    μg, about 9 μg, about 10 μg, about 15 μg, about 20 μg, about 25 μg,    about 30 μg, about 35 μg, about 40 μg, about 45 μg, about 50 μg,    about 55 μg, about 60 μg, about 65 μg, about 70 μg, about 75 μg,    about 80 μg, about 85 μg, about 90 μg, about 95 μg, about 100 μg,    about 110 μg, about 120 μg, about 130 μg, about 140 μg, about 150    μg, about 160 μg, about 170 μg, about 180 μg, about 190 μg, about    200 μg, about 210 μg, about 220 μg, about 230 μg, about 240 μg,    about 250 μg, 260 μg, about 270 μg, about 280 μg, about 290 μg,    about 300 μg, about 310 μg, about 320 μg, about 330 μg, about 340    μg, about 350 μg, 360 μg, about 370 μg, about 380 μg, about 390 μg,    about 400 μg, about 410 μg, about 420 μg, about 430 μg, about 440    μg, about 450 μg, 460 μg, about 470 μg, about 480 μg, about 490 μg,    about 500 μg, about 510 μg, about 520 μg, about 530 μg, about 540    μg, about 550 μg, 560 μg, about 570 μg, about 580 μg, about 590 μg,    about 600 μg, about 610 μg, about 620 μg, about 630 μg, about 640    μg, about 650 μg, 660 μg, about 670 μg, about 680 μg, about 690 μg,    about 700 μg, about 710 μg, about 720 μg, about 730 μg, about 740    μg, about 750 μg, 760 μg, about 770 μg, about 780 μg, about 790 μg,    about 800 μg, about 810 μg, about 820 μg, about 830 μg, about 840    μg, about 850 μg, 860 μg, about 870 μg, about 880 μg, about 890 μg,    about 900 μg, about 910 μg, about 920 μg, about 930 μg, about 940    μg, about 950 μg, 960 μg, about 970 μg, about 980 μg, about 990 μg,    or about 1,000 μg, or in an amount of at least 1 μg, at least 2 μg,    at least 3 μg, at least 4 μg, at least 5 μg, at least 6 μg, at least    7 μg, at least 8 μg, at least 9 μg, at least 10 μg, at least 15 μg,    at least 20 μg, at least 25 μg, at least 30 μg, at least 35 μg, at    least 40 μg, at least 45 μg, at least 50 μg, at least 55 μg, at    least 60 μg, at least 65 μg, at least 70 μg, at least 75 μg, at    least 80 μg, at least 85 μg, at least 90 μg, at least 95 μg, at    least 100 μg, at least 110 μg, at least 120 μg, at least 130 μg, at    least 140 μg, at least 150 μg, at least 160 μg, at least 170 μg, at    least 180 μg, at least 190 μg, at least 200 μg, at least 210 μg, at    least 220 μg, at least 230 μg, at least 240 μg, at least 250 μg, 260    μg, at least 270 μg, at least 280 μg, at least 290 μg, at least 300    μg, at least 310 μg, at least 320 μg, at least 330 μg, at least 340    μg, at least 350 μg, 360 μg, at least 370 μg, at least 380 μg, at    least 390 μg, at least 400 μg, at least 410 μg, at least 420 μg, at    least 430 μg, at least 440 μg, at least 450 μg, 460 μg, at least 470    μg, at least 480 μg, at least 490 μg, at least 500 μg, at least 510    μg, at least 520 μg, at least 530 μg, at least 540 μg, at least 550    μg, 560 μg, at least 570 μg, at least 580 μg, at least 590 μg, at    least 600 μg, at least 610 μg, at least 620 μg, at least 630 μg, at    least 640 μg, at least 650 μg, 660 μg, at least 670 μg, at least 680    μg, at least 690 μg, at least 700 μg, at least 710 μg, at least 720    μg, at least 730 μg, at least 740 μg, at least 750 μg, 760 μg, at    least 770 μg, at least 780 μg, at least 790 μg, at least 800 μg, at    least 810 μg, at least 820 μg, at least 830 μg, at least 840 μg, at    least 850 μg, 860 μg, at least 870 μg, at least 880 μg, at least 890    μg, at least 900 μg, at least 910 μg, at least 920 μg, at least 930    μg, at least 940 μg, at least 950 μg, 960 μg, at least 970 μg, at    least 980 μg, at least 990 μg, or at least 1,000 μg, or in an amount    of at most 1 μg, at most 2 μg, at most 3 μg, at most 4 μg, at most 5    μg, at most 6 μg, at most 7 μg, at most 8 μg, at most 9 μg, at most    10 μg, at most 15 μg, at most 20 μg, at most 25 μg, at most 30 μg,    at most 35 μg, at most 40 μg, at most 45 μg, at most 50 μg, at most    55 μg, at most 60 μg, at most 65 μg, at most 70 μg, at most 75 μg,    at most 80 μg, at most 85 μg, at most 90 μg, at most 95 μg, at most    100 μg, at most 110 μg, at most 120 μg, at most 130 μg, at most 140    μg, at most 150 μg, at most 160 μg, at most 170 μg, at most 180 μg,    at most 190 μg, at most 200 μg, at most 210 μg, at most 220 μg, at    most 230 μg, at most 240 μg, at most 250 μg, 260 μg, at most 270 μg,    at most 280 μg, at most 290 μg, at most 300 μg, at most 310 μg, at    most 320 μg, at most 330 μg, at most 340 μg, at most 350 μg, 360 μg,    at most 370 μg, at most 380 μg, at most 390 μg, at most 400 μg, at    most 410 μg, at most 420 μg, at most 430 μg, at most 440 μg, at most    450 μg, 460 μg, at most 470 μg, at most 480 μg, at most 490 μg, at    most 500 μg, at most 510 μg, at most 520 μg, at most 530 μg, at most    540 μg, at most 550 μg, 560 μg, at most 570 μg, at most 580 μg, at    most 590 μg, at most 600 μg, at most 610 μg, at most 620 μg, at most    630 μg, at most 640 μg, at most 650 μg, 660 μg, at most 670 μg, at    most 680 μg, at most 690 μg, at most 700 μg, at most 710 μg, at most    720 μg, at most 730 μg, at most 740 μg, at most 750 μg, 760 μg, at    most 770 μg, at most 780 μg, at most 790 μg, at most 800 μg, at most    810 μg, at most 820 μg, at most 830 μg, at most 840 μg, at most 850    μg, 860 μg, at most 870 μg, at most 880 μg, at most 890 μg, at most    900 μg, at most 910 μg, at most 920 μg, at most 930 μg, at most 940    μg, at most 950 μg, 960 μg, at most 970 μg, at most 980 μg, at most    990 μg, or at most 1,000 μg.-   101. The pharmaceutical composition of embodiment 99, wherein the    one or more compounds are in an amount of about 1 μg to about 10 μg,    about 1 μg to about 20 μg, about 1 μg to about 30 μg, about 1 μg to    about 40 μg, about 1 μg to about 50 μg, about 1 μg to about 60 μg,    about 1 μg to about 70 μg, about 1 μg to about 80 μg, about 1 μg to    about 90 μg, about 1 μg to about 100 μg, about 1 μg to about 110 μg,    about 1 μg to about 120 μg, about 1 μg to about 130 μg, about 1 μg    to about 140 μg, about 1 μg to about 150 μg, about 5 μg to about 10    μg, about 5 μg to about 20 μg, about 5 μg to about 30 μg, about 5 μg    to about 40 μg, about 5 μg to about 50 μg, about 5 μg to about 60    μg, about 5 μg to about 70 μg, about 5 μg to about 80 μg, about 5 μg    to about 90 μg, about 5 μg to about 100 μg, about 5 μg to about 110    μg, about 5 μg to about 120 μg, about 5 μg to about 130 μg, about 5    μg to about 140 μg, about 5 μg to about 150 μg, about 10 μg to about    20 μg, about 10 μg to about 30 μg, about 10 μg to about 40 μg, about    10 μg to about 50 μg, about 10 μg to about 60 μg, about 10 μg to    about 70 μg, about 10 μg to about 80 μg, about 10 μg to about 90 μg,    about 10 μg to about 100 μg, about 10 μg to about 110 μg, about 10    μg to about 120 μg, about 10 μg to about 130 μg, about 10 μg to    about 140 μg, about 10 μg to about 150 μg, about 10 μg to about 175    μg, about 10 μg to about 200 μg, about 10 μg to about 225 μg, about    10 μg to about 250 μg, about 25 μg to about 50 μg, about 25 μg to    about 75 μg, about 25 μg to about 100 μg, about 25 μg to about 125    μg, about 25 μg to about 150 μg, about 25 μg to about 175 μg, about    25 μg to about 200 μg, about 25 μg to about 225 μg, about 25 μg to    about 250 μg, about 50 μg to about 75 μg, about 50 μg to about 100    μg, about 50 μg to about 125 μg, about 50 μg to about 150 μg, about    50 μg to about 175 μg, about 50 μg to about 200 μg, about 50 μg to    about 225 μg, about 50 μg to about 250 μg, about 75 μg to about 100    μg, about 75 μg to about 125 μg, about 75 μg to about 150 μg, about    75 μg to about 175 μg, about 75 μg to about 200 μg, about 75 μg to    about 225 μg, about 75 μg to about 250 μg, about 100 μg to about 125    μg, about 100 μg to about 150 μg, about 100 μg to about 175 μg,    about 100 μg to about 200 μg, about 100 μg to about 225 μg, about    100 μg to about 250 μg, about 100 μg to about 275 μg, about 100 μg    to about 300 μg, about 100 μg to about 325 μg, about 100 μg to about    350 μg, about 100 μg to about 375 μg, about 100 μg to about 400 μg,    about 100 μg to about 425 μg, about 100 μg to about 450 μg, about    100 μg to about 475 μg, about 100 μg to about 500 μg, about 100 μg    to about 525 μg, about 100 μg to about 550 μg, about 100 μg to about    575 μg, about 100 μg to about 600 μg, about 125 μg to about 150 μg,    about 125 μg to about 175 μg, about 125 μg to about 200 μg, about    125 μg to about 225 μg, about 125 μg to about 250 μg, about 125 μg    to about 275 μg, about 125 μg to about 300 μg, about 125 μg to about    325 μg, about 125 μg to about 350 μg, about 125 μg to about 375 μg,    about 125 μg to about 400 μg, about 125 μg to about 425 μg, about    125 μg to about 450 μg, about 125 μg to about 475 μg, about 125 μg    to about 500 μg, about 125 μg to about 525 μg, about 125 μg to about    550 μg, about 125 μg to about 575 μg, about 125 μg to about 600 μg,    about 150 μg to about 175 μg, about 150 μg to about 200 μg, about    150 μg to about 225 μg, about 150 μg to about 250 μg, about 150 μg    to about 275 μg, about 150 μg to about 300 μg, about 150 μg to about    325 μg, about 150 μg to about 350 μg, about 150 μg to about 375 μg,    about 150 μg to about 400 μg, about 150 μg to about 425 μg, about    150 μg to about 450 μg, about 150 μg to about 475 μg, about 150 μg    to about 500 μg, about 150 μg to about 525 μg, about 150 μg to about    550 μg, about 150 μg to about 575 μg, about 150 μg to about 600 μg,    about 200 μg to about 225 μg, about 200 μg to about 250 μg, about    200 μg to about 275 μg, about 200 μg to about 300 μg, about 200 μg    to about 325 μg, about 200 μg to about 350 μg, about 200 μg to about    375 μg, about 200 μg to about 400 μg, about 200 μg to about 425 μg,    about 200 μg to about 450 μg, about 200 μg to about 475 μg, about    200 μg to about 500 μg, about 200 μg to about 525 μg, about 200 μg    to about 550 μg, about 200 μg to about 575 μg, about 200 μg to about    600 μg, about 200 μg to about 625 μg, about 200 μg to about 650 μg,    about 200 μg to about 675 μg, about 200 μg to about 700 μg, about    200 μg to about 725 μg, about 200 μg to about 750 μg, about 200 μg    to about 775 μg, about 200 μg to about 800 μg, about 200 μg to about    825 μg, about 200 μg to about 850 μg, about 200 μg to about 875 μg,    about 200 μg to about 900 μg, about 200 μg to about 925 μg, about    200 μg to about 950 μg, about 200 μg to about 975 μg, about 200 μg    to about 1,000 μg, about 250 μg to about 275 μg, about 250 μg to    about 300 μg, about 250 μg to about 325 μg, about 250 μg to about    350 μg, about 250 μg to about 375 μg, about 250 μg to about 400 μg,    about 250 μg to about 425 μg, about 250 μg to about 450 μg, about    250 μg to about 475 μg, about 250 μg to about 500 μg, about 250 μg    to about 525 μg, about 250 μg to about 550 μg, about 250 μg to about    575 μg, about 250 μg to about 600 μg, about 250 μg to about 625 μg,    about 250 μg to about 650 μg, about 250 μg to about 675 μg, about    250 μg to about 700 μg, about 250 μg to about 725 μg, about 250 μg    to about 750 μg, about 250 μg to about 775 μg, about 250 μg to about    800 μg, about 250 μg to about 825 μg, about 250 μg to about 850 μg,    about 250 μg to about 875 μg, about 250 μg to about 900 μg, about    250 μg to about 925 μg, about 250 μg to about 950 μg, about 250 μg    to about 975 μg, about 250 μg to about 1,000 μg, about 300 μg to    about 325 μg, about 300 μg to about 350 μg, about 300 μg to about    375 μg, about 300 μg to about 400 μg, about 300 μg to about 425 μg,    about 300 μg to about 450 μg, about 300 μg to about 475 μg, about    300 μg to about 500 μg, about 300 μg to about 525 μg, about 300 μg    to about 550 μg, about 300 μg to about 575 μg, about 300 μg to about    600 μg, about 300 μg to about 625 μg, about 300 μg to about 650 μg,    about 300 μg to about 675 μg, about 300 μg to about 700 μg, about    300 μg to about 725 μg, about 300 μg to about 750 μg, about 300 μg    to about 775 μg, about 300 μg to about 800 μg, about 300 μg to about    825 μg, about 300 μg to about 850 μg, about 300 μg to about 875 μg,    about 300 μg to about 900 μg, about 300 μg to about 925 μg, about    300 μg to about 950 μg, about 300 μg to about 975 μg, about 300 μg    to about 1,000 μg, about 400 μg to about 425 μg, about 400 μg to    about 450 μg, about 400 μg to about 475 μg, about 400 μg to about    500 μg, about 400 μg to about 525 μg, about 400 μg to about 550 μg,    about 400 μg to about 575 μg, about 400 μg to about 600 μg, about    400 μg to about 625 μg, about 400 μg to about 650 μg, about 400 μg    to about 675 μg, about 400 μg to about 700 μg, about 400 μg to about    725 μg, about 400 μg to about 750 μg, about 400 μg to about 775 μg,    about 400 μg to about 800 μg, about 400 μg to about 825 μg, about    400 μg to about 850 μg, about 400 μg to about 875 μg, about 400 μg    to about 900 μg, about 400 μg to about 925 μg, about 400 μg to about    950 μg, about 400 μg to about 975 μg, about 400 μg to about 1,000    μg, about 500 μg to about 525 μg, about 500 μg to about 550 μg,    about 500 μg to about 575 μg, about 500 μg to about 600 μg, about    500 μg to about 625 μg, about 500 μg to about 650 μg, about 500 μg    to about 675 μg, about 500 μg to about 700 μg, about 500 μg to about    725 μg, about 500 μg to about 750 μg, about 500 μg to about 775 μg,    about 500 μg to about 800 μg, about 500 μg to about 825 μg, about    500 μg to about 850 μg, about 500 μg to about 875 μg, about 500 μg    to about 900 μg, about 500 μg to about 925 μg, about 500 μg to about    950 μg, about 500 μg to about 975 μg, about 500 μg to about 1,000    μg, about 600 μg to about 625 μg, about 600 μg to about 650 μg,    about 600 μg to about 675 μg, about 600 μg to about 700 μg, about    600 μg to about 725 μg, about 600 μg to about 750 μg, about 600 μg    to about 775 μg, about 600 μg to about 800 μg, about 600 μg to about    825 μg, about 600 μg to about 850 μg, about 600 μg to about 875 μg,    about 600 μg to about 900 μg, about 600 μg to about 925 μg, about    600 μg to about 950 μg, about 600 μg to about 975 μg, about 600 μg    to about 1,000 μg, about 700 μg to about 725 μg, about 700 μg to    about 750 μg, about 700 μg to about 775 μg, about 700 μg to about    800 μg, about 700 μg to about 825 μg, about 700 μg to about 850 μg,    about 700 μg to about 875 μg, about 700 μg to about 900 μg, about    700 μg to about 925 μg, about 700 μg to about 950 μg, about 700 μg    to about 975 μg, about 700 μg to about 1,000 μg, about 800 μg to    about 825 μg, about 800 μg to about 850 μg, about 800 μg to about    875 μg, about 800 μg to about 900 μg, about 800 μg to about 925 μg,    about 800 μg to about 950 μg, about 800 μg to about 975 μg, or about    800 μg to about 1,000 μg.-   102. The pharmaceutical composition of embodiment 99, wherein the    one or more compounds are in an amount of about 1 mg, about 2 mg,    about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8    mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg,    about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,    about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg,    about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg,    about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150    mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about    200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg,    about 250 mg, 260 mg, about 270 mg, about 280 mg, about 290 mg,    about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340    mg, about 350 mg, 360 mg, about 370 mg, about 380 mg, about 390 mg,    about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440    mg, about 450 mg, 460 mg, about 470 mg, about 480 mg, about 490 mg,    about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540    mg, about 550 mg, 560 mg, about 570 mg, about 580 mg, about 590 mg,    about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640    mg, about 650 mg, 660 mg, about 670 mg, about 680 mg, about 690 mg,    about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740    mg, about 750 mg, 760 mg, about 770 mg, about 780 mg, about 790 mg,    about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840    mg, about 850 mg, 860 mg, about 870 mg, about 880 mg, about 890 mg,    about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940    mg, about 950 mg, 960 mg, about 970 mg, about 980 mg, about 990 mg,    or about 1,000 mg, or in an amount of at least 1 mg, at least 2 mg,    at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least    7 mg, at least 8 mg, at least 9 mg, at least 10 mg, at least 15 mg,    at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at    least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at    least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at    least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at    least 100 mg, at least 110 mg, at least 120 mg, at least 130 mg, at    least 140 mg, at least 150 mg, at least 160 mg, at least 170 mg, at    least 180 mg, at least 190 mg, at least 200 mg, at least 210 mg, at    least 220 mg, at least 230 mg, at least 240 mg, at least 250 mg, 260    mg, at least 270 mg, at least 280 mg, at least 290 mg, at least 300    mg, at least 310 mg, at least 320 mg, at least 330 mg, at least 340    mg, at least 350 mg, 360 mg, at least 370 mg, at least 380 mg, at    least 390 mg, at least 400 mg, at least 410 mg, at least 420 mg, at    least 430 mg, at least 440 mg, at least 450 mg, 460 mg, at least 470    mg, at least 480 mg, at least 490 mg, at least 500 mg, at least 510    mg, at least 520 mg, at least 530 mg, at least 540 mg, at least 550    mg, 560 mg, at least 570 mg, at least 580 mg, at least 590 mg, at    least 600 mg, at least 610 mg, at least 620 mg, at least 630 mg, at    least 640 mg, at least 650 mg, 660 mg, at least 670 mg, at least 680    mg, at least 690 mg, at least 700 mg, at least 710 mg, at least 720    mg, at least 730 mg, at least 740 mg, at least 750 mg, 760 mg, at    least 770 mg, at least 780 mg, at least 790 mg, at least 800 mg, at    least 810 mg, at least 820 mg, at least 830 mg, at least 840 mg, at    least 850 mg, 860 mg, at least 870 mg, at least 880 mg, at least 890    mg, at least 900 mg, at least 910 mg, at least 920 mg, at least 930    mg, at least 940 mg, at least 950 mg, 960 mg, at least 970 mg, at    least 980 mg, at least 990 mg, or at least 1,000 mg, or in an amount    of at most 1 mg, at most 2 mg, at most 3 mg, at most 4 mg, at most 5    mg, at most 6 mg, at most 7 mg, at most 8 mg, at most 9 mg, at most    10 mg, at most 15 mg, at most 20 mg, at most 25 mg, at most 30 mg,    at most 35 mg, at most 40 mg, at most 45 mg, at most 50 mg, at most    55 mg, at most 60 mg, at most 65 mg, at most 70 mg, at most 75 mg,    at most 80 mg, at most 85 mg, at most 90 mg, at most 95 mg, at most    100 mg, at most 110 mg, at most 120 mg, at most 130 mg, at most 140    mg, at most 150 mg, at most 160 mg, at most 170 mg, at most 180 mg,    at most 190 mg, at most 200 mg, at most 210 mg, at most 220 mg, at    most 230 mg, at most 240 mg, at most 250 mg, 260 mg, at most 270 mg,    at most 280 mg, at most 290 mg, at most 300 mg, at most 310 mg, at    most 320 mg, at most 330 mg, at most 340 mg, at most 350 mg, 360 mg,    at most 370 mg, at most 380 mg, at most 390 mg, at most 400 mg, at    most 410 mg, at most 420 mg, at most 430 mg, at most 440 mg, at most    450 mg, 460 mg, at most 470 mg, at most 480 mg, at most 490 mg, at    most 500 mg, at most 510 mg, at most 520 mg, at most 530 mg, at most    540 mg, at most 550 mg, 560 mg, at most 570 mg, at most 580 mg, at    most 590 mg, at most 600 mg, at most 610 mg, at most 620 mg, at most    630 mg, at most 640 mg, at most 650 mg, 660 mg, at most 670 mg, at    most 680 mg, at most 690 mg, at most 700 mg, at most 710 mg, at most    720 mg, at most 730 mg, at most 740 mg, at most 750 mg, 760 mg, at    most 770 mg, at most 780 mg, at most 790 mg, at most 800 mg, at most    810 mg, at most 820 mg, at most 830 mg, at most 840 mg, at most 850    mg, 860 mg, at most 870 mg, at most 880 mg, at most 890 mg, at most    900 mg, at most 910 mg, at most 920 mg, at most 930 mg, at most 940    mg, at most 950 mg, 960 mg, at most 970 mg, at most 980 mg, at most    990 mg, or at most 1,000 mg.-   103. The pharmaceutical composition of embodiment 99, wherein the    one or more compounds are in an amount of about 1 mg to about 10 mg,    about 1 mg to about 20 mg, about 1 mg to about 30 mg, about 1 mg to    about 40 mg, about 1 mg to about 50 mg, about 1 mg to about 60 mg,    about 1 mg to about 70 mg, about 1 mg to about 80 mg, about 1 mg to    about 90 mg, about 1 mg to about 100 mg, about 1 mg to about 110 mg,    about 1 mg to about 120 mg, about 1 mg to about 130 mg, about 1 mg    to about 140 mg, about 1 mg to about 150 mg, about 5 mg to about 10    mg, about 5 mg to about 20 mg, about 5 mg to about 30 mg, about 5 mg    to about 40 mg, about 5 mg to about 50 mg, about 5 mg to about 60    mg, about 5 mg to about 70 mg, about 5 mg to about 80 mg, about 5 mg    to about 90 mg, about 5 mg to about 100 mg, about 5 mg to about 110    mg, about 5 mg to about 120 mg, about 5 mg to about 130 mg, about 5    mg to about 140 mg, about 5 mg to about 150 mg, about 10 mg to about    20 mg, about 10 mg to about 30 mg, about 10 mg to about 40 mg, about    10 mg to about 50 mg, about 10 mg to about 60 mg, about 10 mg to    about 70 mg, about 10 mg to about 80 mg, about 10 mg to about 90 mg,    about 10 mg to about 100 mg, about 10 mg to about 110 mg, about 10    mg to about 120 mg, about 10 mg to about 130 mg, about 10 mg to    about 140 mg, about 10 mg to about 150 mg, about 10 mg to about 175    mg, about 10 mg to about 200 mg, about 10 mg to about 225 mg, about    10 mg to about 250 mg, about 25 mg to about 50 mg, about 25 mg to    about 75 mg, about 25 mg to about 100 mg, about 25 mg to about 125    mg, about 25 mg to about 150 mg, about 25 mg to about 175 mg, about    25 mg to about 200 mg, about 25 mg to about 225 mg, about 25 mg to    about 250 mg, about 50 mg to about 75 mg, about 50 mg to about 100    mg, about 50 mg to about 125 mg, about 50 mg to about 150 mg, about    50 mg to about 175 mg, about 50 mg to about 200 mg, about 50 mg to    about 225 mg, about 50 mg to about 250 mg, about 75 mg to about 100    mg, about 75 mg to about 125 mg, about 75 mg to about 150 mg, about    75 mg to about 175 mg, about 75 mg to about 200 mg, about 75 mg to    about 225 mg, about 75 mg to about 250 mg, about 100 mg to about 125    mg, about 100 mg to about 150 mg, about 100 mg to about 175 mg,    about 100 mg to about 200 mg, about 100 mg to about 225 mg, about    100 mg to about 250 mg, about 100 mg to about 275 mg, about 100 mg    to about 300 mg, about 100 mg to about 325 mg, about 100 mg to about    350 mg, about 100 mg to about 375 mg, about 100 mg to about 400 mg,    about 100 mg to about 425 mg, about 100 mg to about 450 mg, about    100 mg to about 475 mg, about 100 mg to about 500 mg, about 100 mg    to about 525 mg, about 100 mg to about 550 mg, about 100 mg to about    575 mg, about 100 mg to about 600 mg, about 125 mg to about 150 mg,    about 125 mg to about 175 mg, about 125 mg to about 200 mg, about    125 mg to about 225 mg, about 125 mg to about 250 mg, about 125 mg    to about 275 mg, about 125 mg to about 300 mg, about 125 mg to about    325 mg, about 125 mg to about 350 mg, about 125 mg to about 375 mg,    about 125 mg to about 400 mg, about 125 mg to about 425 mg, about    125 mg to about 450 mg, about 125 mg to about 475 mg, about 125 mg    to about 500 mg, about 125 mg to about 525 mg, about 125 mg to about    550 mg, about 125 mg to about 575 mg, about 125 mg to about 600 mg,    about 150 mg to about 175 mg, about 150 mg to about 200 mg, about    150 mg to about 225 mg, about 150 mg to about 250 mg, about 150 mg    to about 275 mg, about 150 mg to about 300 mg, about 150 mg to about    325 mg, about 150 mg to about 350 mg, about 150 mg to about 375 mg,    about 150 mg to about 400 mg, about 150 mg to about 425 mg, about    150 mg to about 450 mg, about 150 mg to about 475 mg, about 150 mg    to about 500 mg, about 150 mg to about 525 mg, about 150 mg to about    550 mg, about 150 mg to about 575 mg, about 150 mg to about 600 mg,    about 200 mg to about 225 mg, about 200 mg to about 250 mg, about    200 mg to about 275 mg, about 200 mg to about 300 mg, about 200 mg    to about 325 mg, about 200 mg to about 350 mg, about 200 mg to about    375 mg, about 200 mg to about 400 mg, about 200 mg to about 425 mg,    about 200 mg to about 450 mg, about 200 mg to about 475 mg, about    200 mg to about 500 mg, about 200 mg to about 525 mg, about 200 mg    to about 550 mg, about 200 mg to about 575 mg, about 200 mg to about    600 mg, about 200 mg to about 625 mg, about 200 mg to about 650 mg,    about 200 mg to about 675 mg, about 200 mg to about 700 mg, about    200 mg to about 725 mg, about 200 mg to about 750 mg, about 200 mg    to about 775 mg, about 200 mg to about 800 mg, about 200 mg to about    825 mg, about 200 mg to about 850 mg, about 200 mg to about 875 mg,    about 200 mg to about 900 mg, about 200 mg to about 925 mg, about    200 mg to about 950 mg, about 200 mg to about 975 mg, about 200 mg    to about 1,000 mg, about 250 mg to about 275 mg, about 250 mg to    about 300 mg, about 250 mg to about 325 mg, about 250 mg to about    350 mg, about 250 mg to about 375 mg, about 250 mg to about 400 mg,    about 250 mg to about 425 mg, about 250 mg to about 450 mg, about    250 mg to about 475 mg, about 250 mg to about 500 mg, about 250 mg    to about 525 mg, about 250 mg to about 550 mg, about 250 mg to about    575 mg, about 250 mg to about 600 mg, about 250 mg to about 625 mg,    about 250 mg to about 650 mg, about 250 mg to about 675 mg, about    250 mg to about 700 mg, about 250 mg to about 725 mg, about 250 mg    to about 750 mg, about 250 mg to about 775 mg, about 250 mg to about    800 mg, about 250 mg to about 825 mg, about 250 mg to about 850 mg,    about 250 mg to about 875 mg, about 250 mg to about 900 mg, about    250 mg to about 925 mg, about 250 mg to about 950 mg, about 250 mg    to about 975 mg, about 250 mg to about 1,000 mg, about 300 mg to    about 325 mg, about 300 mg to about 350 mg, about 300 mg to about    375 mg, about 300 mg to about 400 mg, about 300 mg to about 425 mg,    about 300 mg to about 450 mg, about 300 mg to about 475 mg, about    300 mg to about 500 mg, about 300 mg to about 525 mg, about 300 mg    to about 550 mg, about 300 mg to about 575 mg, about 300 mg to about    600 mg, about 300 mg to about 625 mg, about 300 mg to about 650 mg,    about 300 mg to about 675 mg, about 300 mg to about 700 mg, about    300 mg to about 725 mg, about 300 mg to about 750 mg, about 300 mg    to about 775 mg, about 300 mg to about 800 mg, about 300 mg to about    825 mg, about 300 mg to about 850 mg, about 300 mg to about 875 mg,    about 300 mg to about 900 mg, about 300 mg to about 925 mg, about    300 mg to about 950 mg, about 300 mg to about 975 mg, about 300 mg    to about 1,000 mg, about 400 mg to about 425 mg, about 400 mg to    about 450 mg, about 400 mg to about 475 mg, about 400 mg to about    500 mg, about 400 mg to about 525 mg, about 400 mg to about 550 mg,    about 400 mg to about 575 mg, about 400 mg to about 600 mg, about    400 mg to about 625 mg, about 400 mg to about 650 mg, about 400 mg    to about 675 mg, about 400 mg to about 700 mg, about 400 mg to about    725 mg, about 400 mg to about 750 mg, about 400 mg to about 775 mg,    about 400 mg to about 800 mg, about 400 mg to about 825 mg, about    400 mg to about 850 mg, about 400 mg to about 875 mg, about 400 mg    to about 900 mg, about 400 mg to about 925 mg, about 400 mg to about    950 mg, about 400 mg to about 975 mg, about 400 mg to about 1,000    mg, about 500 mg to about 525 mg, about 500 mg to about 550 mg,    about 500 mg to about 575 mg, about 500 mg to about 600 mg, about    500 mg to about 625 mg, about 500 mg to about 650 mg, about 500 mg    to about 675 mg, about 500 mg to about 700 mg, about 500 mg to about    725 mg, about 500 mg to about 750 mg, about 500 mg to about 775 mg,    about 500 mg to about 800 mg, about 500 mg to about 825 mg, about    500 mg to about 850 mg, about 500 mg to about 875 mg, about 500 mg    to about 900 mg, about 500 mg to about 925 mg, about 500 mg to about    950 mg, about 500 mg to about 975 mg, about 500 mg to about 1,000    mg, about 600 mg to about 625 mg, about 600 mg to about 650 mg,    about 600 mg to about 675 mg, about 600 mg to about 700 mg, about    600 mg to about 725 mg, about 600 mg to about 750 mg, about 600 mg    to about 775 mg, about 600 mg to about 800 mg, about 600 mg to about    825 mg, about 600 mg to about 850 mg, about 600 mg to about 875 mg,    about 600 mg to about 900 mg, about 600 mg to about 925 mg, about    600 mg to about 950 mg, about 600 mg to about 975 mg, about 600 mg    to about 1,000 mg, about 700 mg to about 725 mg, about 700 mg to    about 750 mg, about 700 mg to about 775 mg, about 700 mg to about    800 mg, about 700 mg to about 825 mg, about 700 mg to about 850 mg,    about 700 mg to about 875 mg, about 700 mg to about 900 mg, about    700 mg to about 925 mg, about 700 mg to about 950 mg, about 700 mg    to about 975 mg, about 700 mg to about 1,000 mg, about 800 mg to    about 825 mg, about 800 mg to about 850 mg, about 800 mg to about    875 mg, about 800 mg to about 900 mg, about 800 mg to about 925 mg,    about 800 mg to about 950 mg, about 800 mg to about 975 mg, or about    800 mg to about 1,000 mg.-   104. The pharmaceutical composition of any one of embodiments    99-103, wherein the one or more compounds are in an amount of 0.01%,    0.025%, 0.05%, 0.075%, 0.1%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%,    0.7%, 0.75%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%. 9%, 10%,    15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% by weight of the    composition, or at least 0.01%, at least 0.025%, at least 0.05%, at    least 0.075%, at least 0.1%, at least 0.25%, at least 0.5%, at least    0.75%, at least 1%, at least 2%, at least 3%, at least 4%, at least    5%, at least 6%, at least 7%, at least 8%, at least 9%, least 10%,    least 15%, least 20%, least 25%, least 30%, least 35%, least 40%, at    least 45%, or at least 50% by weight of the composition, or at most    0.01%, at most 0.025%, at most 0.05%, at most 0.075%, at most 0.1%,    at most 0.25%, at most 0.5%, at most 0.75%, at most 1%, at most 2%,    at most 3%, at most 4%, at most 5%, at most 6%, at most 7%, at most    8%, at most 9%, at most 10%, at most 15%, at most 20%, at most 25%,    at most 30%, at most 35%, at most 40%, at most 45%, or at most 50%    by weight of the composition.-   105. The pharmaceutical composition of any one of embodiments    99-103, wherein the one or more compounds are in an amount of 0.01%    to about 0.05%, 0.01% to about 0.075%, 0.01% to about 0.1%, about    0.1% to about 0.5%, about 0.1% to about 0.75%, about 0.1% to about    1%, about 0.1% to about 2%, about 0.1% to about 3%, about 0.1% to    about 4%, about 0.1% to about 5%, about 0.1% to about 6%, about 0.1%    to about 7%, about 0.1% to about 8%, about 0.1% to about 9%, about    0.1% to about 10%, about 0.1% to about 15%, about 0.1% to about 20%,    about 0.1% to about 25%, about 0.1% to about 30%, about 0.1% to    about 35%, about 0.1% to about 40%, about 0.25% to about 0.5%, about    0.25% to about 0.75%, about 0.25% to about 1%, about 0.25% to about    2%, about 0.25% to about 3%, about 0.25% to about 4%, about 0.25% to    about 5%, about 0.25% to about 6%, about 0.25% to about 7%, about    0.25% to about 8%, about 0.25% to about 9%, about 0.25% to about    10%, about 0.25% to about 15%, about 0.25% to about 20%, about 0.25%    to about 25%, about 0.25% to about 30%, about 0.25% to about 35%,    about 0.25% to about 40%, about 0.5% to about 0.75%, about 0.5% to    about 1%, about 0.5% to about 2%, about 0.5% to about 3%, about 0.5%    to about 4%, about 0.5% to about 5%, about 0.5% to about 6%, about    0.5% to about 7%, about 0.5% to about 8%, about 0.5% to about 9%,    about 0.5% to about 10%, about 0.5% to about 15%, about 0.5% to    about 20%, about 0.5% to about 25%, about 0.5% to about 30%, about    0.5% to about 35%, about 0.5% to about 40%, about 0.75% to about 1%,    about 0.75% to about 2%, about 0.75% to about 3%, about 0.75% to    about 4%, about 0.75% to about 5%, about 0.75% to about 6%, about    0.75% to about 7%, about 0.75% to about 8%, about 0.75% to about 9%,    about 0.75% to about 10%, about 0.75% to about 15%, about 0.75% to    about 20%, about 0.75% to about 25%, about 0.75% to about 30%, about    0.75% to about 35%, about 0.75% to about 40%, about 1% to about 2%,    about 1% to about 3%, about 1% to about 4%, about 1% to about 5%,    about 1% to about 6%, about 1% to about 7%, about 1% to about 8%,    about 1% to about 9%, about 1% to about 10%, about 1% to about 15%,    about 1% to about 20%, about 1% to about 25%, about 1% to about 30%,    about 1% to about 35%, about 1% to about 40%, about 2% to about 3%,    about 2% to about 4%, about 2% to about 5%, about 2% to about 6%,    about 2% to about 7%, about 2% to about 8%, about 2% to about 9%,    about 2% to about 10%, about 2% to about 15%, about 2% to about 20%,    about 2% to about 25%, about 2% to about 30%, about 2% to about 35%,    about 2% to about 40%, about 3% to about 4%, about 3% to about 5%,    about 3% to about 6%, about 3% to about 7%, about 3% to about 8%,    about 3% to about 9%, about 3% to about 10%, about 3% to about 15%,    about 3% to about 20%, about 3% to about 25%, about 3% to about 30%,    about 3% to about 35%, about 3% to about 40%, about 4% to about 5%,    about 4% to about 6%, about 4% to about 7%, about 4% to about 8%,    about 4% to about 9%, about 4% to about 10%, about 4% to about 15%,    about 4% to about 20%, about 4% to about 25%, about 4% to about 30%,    about 4% to about 35%, about 4% to about 40%, about 5% to about 6%,    about 5% to about 7%, about 5% to about 8%, about 5% to about 9%,    about 5% to about 10%, about 5% to about 15%, about 5% to about 20%,    about 5% to about 25%, about 5% to about 30%, about 5% to about 35%,    about 5% to about 40%, about 6% to about 7%, about 6% to about 8%,    about 6% to about 9%, about 6% to about 10%, about 6% to about 15%,    about 6% to about 20%, about 6% to about 25%, about 6% to about 30%,    about 6% to about 35%, about 6% to about 40%, about 7% to about 8%,    about 7% to about 9%, about 7% to about 10%, about 7% to about 15%,    about 7% to about 20%, about 7% to about 25%, about 7% to about 30%,    about 7% to about 35%, about 7% to about 40%, about 8% to about 9%,    about 8% to about 10%, about 8% to about 15%, about 8% to about 20%,    about 8% to about 25%, about 8% to about 30%, about 8% to about 35%,    about 8% to about 40%, about 9% to about 10%, about 9% to about 15%,    about 9% to about 20%, about 9% to about 25%, about 9% to about 30%,    about 9% to about 35%, about 9% to about 40%, about 10% to about    15%, about 10% to about 20%, about 10% to about 25%, about 10% to    about 30%, about 10% to about 35%, about 10% to about 40%, about 10%    to about 45%, about 10% to about 50%, about 15% to about 20%, about    15% to about 25%, about 15% to about 30%, about 15% to about 35%,    about 15% to about 40%, about 15% to about 45%, about 15% to about    50%, about 20% to about 25%, about 20% to about 30%, about 20% to    about 35%, about 20% to about 40%, about 20% to about 45%, about 20%    to about 50%, about 25% to about 30%, about 25% to about 35%, about    25% to about 40%, about 25% to about 45%, about 30% to about 25%,    about 30% to about 35%, about 30% to about 40%, about 30% to about    45%, about 30% to about 50%, about 35% to about 40%, about 35% to    about 45%, about 35% to about 50%, about 40% to about 45%, about 40%    to about 50%, or about 45% to about 50%, by weight of the    composition.-   106. The pharmaceutical composition of any one of embodiments    99-105, further comprising one or more pharmaceutically acceptable    carriers.-   107. The pharmaceutical composition of embodiment 106, wherein the    one or more pharmaceutically acceptable carriers are in an amount of    at least 25%, at least 30%, at least 35%, at least 40%, at least    45%, at least 50%, at least 55%, at least 60%, at least 65%, at    least 70%, at least 75%, at least 80%, at least 85%, at least 90%,    at least 95%, at least 96%, at least 97%, at least 98% or at least    99% by weight of the composition, or at most 25%, at most 30%, at    most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at    most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at    most 85%, at most 90%, at most 95%, at most 96%, at most 97%, at    most 98% or at most 99% by weight of the composition, or about 25%    to about 50%, about 25% to about 75%, about 25% to about 90%, about    25% to about 95%, about 25% to about 96%, about 25% to about 97%,    about 25% to about 98%, about 25% to about 99%, about 50% to about    75%, about 50% to about 90%, about 50% to about 95%, about 50% to    about 96%, about 50% to about 97%, about 50% to about 98%, about 50%    to about 99%, about 75% to about 80%, about 75% to about 85%, about    75% to about 90%, about 75% to about 95%, about 75% to about 96%,    about 75% to about 97%, about 75% to about 98%, about 75% to about    99%, about 80% to about 85%, about 80% to about 90%, about 80% to    about 95%, about 80% to about 96%, about 80% to about 97%, about 80%    to about 98%, about 80% to about 99%, about 85% to about 90%, about    85% to about 95%, about 85% to about 96%, about 85% to about 97%,    about 85% to about 98%, about 85% to about 99%, about 90% to about    95%, about 90% to about 96%, about 90% to about 97%, about 90% to    about 98%, about 90% to about 99%, or about 95% to about 99%, by    weight of the composition.-   108. The pharmaceutical composition of any one of embodiments    99-107, further comprising one or more pharmaceutically acceptable    components.-   109. The pharmaceutical composition of embodiment 108, wherein the    one or more pharmaceutically acceptable components include one or    more buffers, one or more preservatives, one or more tonicity    adjusters, one or more salts, one or more antioxidants, one or more    osmolality adjusting agents, one or more physiological substances,    one or more pharmacological substances, one or more bulking agents,    one or more viscosity agents, one or more surfactants, one or more    emulsifying agents, one or more wetting agents, one or more    sweetening or flavoring agents.-   110. The pharmaceutical composition of any one of embodiments    99-109, formulated as a topical formulation.-   111. The pharmaceutical composition of embodiment 110, wherein the    topical formulation is a single-phase formulation or a biphasic    formulation.-   112. The pharmaceutical composition of embodiment 110, wherein the    topical formulation is a liquid composition, a colloidal    composition, a semi-solid composition, or a solid composition.-   113. The pharmaceutical composition of embodiment 110, wherein the    topical formulation is a liquid aerosol, a foam, an emulsion, a gel,    a sol, or a solid sol.-   114. The pharmaceutical composition of embodiment 110, wherein the    topical formulation is a spray, a liquid aerosol, a wash, an    aftershave, a perfume, a lotion, a cream, a salve, a waxing    composition, a mousse, a shampoo, a conditioner, an ointment, a    liniment, a paste, a jelly, a soap, a suspension, or an emollient.-   115. A kit comprising a pharmaceutical composition as defined in any    one of Claims 99-114.-   116. The kit of embodiment 115, further comprising a delivery    system.-   117. A method of treating hair loss in an individual comprising the    step of administering a therapeutically effective amount of a    compound as defined in any one of embodiments 1-98 or a    pharmaceutical composition as defined in any one of embodiments    99-114 to the individual.-   118. A method of treating hair thinning in an individual comprising    the step of administering a therapeutically effective amount of a    compound as defined in any one of embodiments 1-98 or a    pharmaceutical composition as defined in any one of embodiments    99-114 to the individual.-   119. A method of treating hair color loss in an individual    comprising the step of administering a therapeutically effective    amount of a compound as defined in any one of embodiments 1-98 or a    pharmaceutical composition as defined in any one of embodiments    99-114 to the individual.-   120. A method of treating a condition associated with a degenerative    hair follicle disorder in an individual comprising the step of    administering a therapeutically effective amount of a compound as    defined in any one of embodiments 1-98 or a pharmaceutical    composition as defined in any one of embodiments 99-114 to the    individual.-   121. The method of embodiment 120, wherein the degenerative hair    follicle disorder is associated with hair loss, hair thinning, hair    color loss, no new hair shaft growth, reduced rate of hair shaft    growth, reduced hair shaft diameter (thickness), reduced hair shaft    length, reduced hair density, reduced keratinization of the hair    shaft, increased fragility, reduced hair pigmentation, reduced hair    shaft luster, reduced hair health, reduced time a hair follicle    spends in anagen phase, reduced time a hair follicle spends in    catagen phase, reduced time a hair follicle spends in telogen phase,    premature release of hair shaft from hair follicle, premature    initiation of apoptosis in hair follicle, premature conversion of a    terminal hair into a vellus hair.-   122. The method of embodiment 120, wherein the degenerative hair    follicle disorder is associated with a scarring alopecias or a    non-scarring alopecia.-   123. The method of embodiment 122, wherein the scarring alopecia    includes bullous diseases, chemical alopecia, discoid lupus    erythematosus, severre folliculitis, lichen planopilaris, dissecting    cellulitis, central centrifugal cicatricial alopecia, postmenopausal    frontal fibrosing alopecia, a tumor or a skin outgrowth.-   124. The method of embodiment 122, wherein the nonscarring alopecia    includes anagen effluvium, alopecia adnata, alopecia androgenetica,    alopecian AREata, alopecia congenitalis, alopecia diffusa, alopecia    disseminate, alopecia follicularis, alopecia leprotica, alopecia    marginalis, alopecia medicamentosa, alopecia mucinosa, alopecia    neurotica, alopecia pityrodes, alopecia presenili, alopecia senilis,    alopecia symptomatica, alopecia syphilitica, alopecia totalis,    alopecia toxica, alopecia triangularis, alopecia triangularis    congenitalis, alopecia universalis, folliculitis, olliculitis    decalvans, traction alopecia, trichotillomania, telogen effluvium,    or inherited disorders of the hair shaft.-   125. A method of improving hair appearance in an individual    comprising the step of administering a therapeutically effective    amount of a compound as defined in any one of embodiments 1-98 or a    pharmaceutical composition as defined in any one of embodiments    99-114 to the individual.-   126. A method of treating a skin condition in an individual    comprising the step of administering a therapeutically effective    amount of a compound as defined in any one of embodiments 1-98 or a    pharmaceutical composition as defined in any one of embodiments    99-114 to the individual.-   127. The method of embodiment 126, wherein the skin condition    includes an acne, an excessive sebum production, a post-wound scar    formation, or a dermatological issue associated with polycystic    ovary disease.-   128. A method according to any one of embodiments 117-127, wherein    the therapeutically effective amount of a compound is at least 0.001    mg/kg/day, at least 0.01 mg/kg/day, at least 0.1 mg/kg/day, at least    1.0 mg/kg/day, at least 5.0 mg/kg/day, at least 10 mg/kg/day, at    least 15 mg/kg/day, at least 20 mg/kg/day, at least 25 mg/kg/day, at    least 30 mg/kg/day, at least 35 mg/kg/day, at least 40 mg/kg/day, at    least 45 mg/kg/day, or at least 50 mg/kg/day or at most 0.001    mg/kg/day, at most 0.01 mg/kg/day, at most 0.1 mg/kg/day, at most    1.0 mg/kg/day, at most 5.0 mg/kg/day, at most 10 mg/kg/day, at most    15 mg/kg/day, at most 20 mg/kg/day, at most 25 mg/kg/day, at most 30    mg/kg/day, at most 35 mg/kg/day, at most 40 mg/kg/day, at most 45    mg/kg/day, or at most 50 mg/kg/day, or about 0.001 mg/kg/day to    about 10 mg/kg/day, about 0.001 mg/kg/day to about 15 mg/kg/day,    about 0.001 mg/kg/day to about 20 mg/kg/day, about 0.001 mg/kg/day    to about 25 mg/kg/day, about 0.001 mg/kg/day to about 30 mg/kg/day,    about 0.001 mg/kg/day to about 35 mg/kg/day, about 0.001 mg/kg/day    to about 40 mg/kg/day, about 0.001 mg/kg/day to about 45 mg/kg/day,    about 0.001 mg/kg/day to about 50 mg/kg/day, about 0.001 mg/kg/day    to about 75 mg/kg/day, or about 0.001 mg/kg/day to about 100    mg/kg/day. In yet other aspects of this embodiment, an effective    amount of an ARE disclosed herein may be in the range of, e.g.,    about 0.01 mg/kg/day to about 10 mg/kg/day, about 0.01 mg/kg/day to    about 15 mg/kg/day, about 0.01 mg/kg/day to about 20 mg/kg/day,    about 0.01 mg/kg/day to about 25 mg/kg/day, about 0.01 mg/kg/day to    about 30 mg/kg/day, about 0.01 mg/kg/day to about 35 mg/kg/day,    about 0.01 mg/kg/day to about 40 mg/kg/day, about 0.01 mg/kg/day to    about 45 mg/kg/day, about 0.01 mg/kg/day to about 50 mg/kg/day,    about 0.01 mg/kg/day to about 75 mg/kg/day, or about 0.01 mg/kg/day    to about 100 mg/kg/day. In still other aspects of this embodiment,    an effective amount of an ARE disclosed herein may be in the range    of, e.g., about 0.1 mg/kg/day to about 10 mg/kg/day, about 0.1    mg/kg/day to about 15 mg/kg/day, about 0.1 mg/kg/day to about 20    mg/kg/day, about 0.1 mg/kg/day to about 25 mg/kg/day, about 0.1    mg/kg/day to about 30 mg/kg/day, about 0.1 mg/kg/day to about 35    mg/kg/day, about 0.1 mg/kg/day to about 40 mg/kg/day, about 0.1    mg/kg/day to about 45 mg/kg/day, about 0.1 mg/kg/day to about 50    mg/kg/day, about 0.1 mg/kg/day to about 75 mg/kg/day, about 0.1    mg/kg/day to about 100 mg/kg/day, about 1 mg/kg/day to about 10    mg/kg/day, about 1 mg/kg/day to about 15 mg/kg/day, about 1    mg/kg/day to about 20 mg/kg/day, about 1 mg/kg/day to about 25    mg/kg/day, about 1 mg/kg/day to about 30 mg/kg/day, about 1    mg/kg/day to about 35 mg/kg/day, about 1 mg/kg/day to about 40    mg/kg/day, about 1 mg/kg/day to about 45 mg/kg/day, about 1    mg/kg/day to about 50 mg/kg/day, about 1 mg/kg/day to about 75    mg/kg/day, or about 1 mg/kg/day to about 100 mg/kg/day. In yet other    aspects of this embodiment, an effective amount of an ARE disclosed    herein may be in the range of, e.g., about 5 mg/kg/day to about 10    mg/kg/day, about 5 mg/kg/day to about 15 mg/kg/day, about 5    mg/kg/day to about 20 mg/kg/day, about 5 mg/kg/day to about 25    mg/kg/day, about 5 mg/kg/day to about 30 mg/kg/day, about 5    mg/kg/day to about 35 mg/kg/day, about 5 mg/kg/day to about 40    mg/kg/day, about 5 mg/kg/day to about 45 mg/kg/day, about 5    mg/kg/day to about 50 mg/kg/day, about 5 mg/kg/day to about 75    mg/kg/day, or about 5 mg/kg/day to about 100 mg/kg/day.-   129. A method according to any one of embodiments 117-127, wherein    the therapeutically effective amount of a compound is at least 0.001    mg/day, at least 0.01 mg/day, at least 0.1 mg/day, at least 1.0    mg/day, at least 5.0 mg/day, at least 10 mg/day, at least 15 mg/day,    at least 20 mg/day, at least 25 mg/day, at least 30 mg/day, at least    35 mg/day, at least 40 mg/day, at least 45 mg/day, or at least 50    mg/day, or at most 0.001 mg/day, at most 0.01 mg/day, at most 0.1    mg/day, at most 1.0 mg/day, at most 5.0 mg/day, at most 10 mg/day,    at most 15 mg/day, at most 20 mg/day, at most 25 mg/day, at most 30    mg/day, at most 35 mg/day, at most 40 mg/day, at most 45 mg/day, or    at most 50 mg/day, or about 0.001 mg/day to about 10 mg/day, about    0.001 mg/day to about 15 mg/day, about 0.001 mg/day to about 20    mg/day, about 0.001 mg/day to about 25 mg/day, about 0.001 mg/day to    about 30 mg/day, about 0.001 mg/day to about 35 mg/day, about 0.001    mg/day to about 40 mg/day, about 0.001 mg/day to about 45 mg/day,    about 0.001 mg/day to about 50 mg/day, about 0.001 mg/day to about    75 mg/day, or about 0.001 mg/day to about 100 mg/day. In yet other    aspects of this embodiment, an effective amount of an ARE disclosed    herein may be in the range of, e.g., about 0.01 mg/day to about 10    mg/day, about 0.01 mg/day to about 15 mg/day, about 0.01 mg/day to    about 20 mg/day, about 0.01 mg/day to about 25 mg/day, about 0.01    mg/day to about 30 mg/day, about 0.01 mg/day to about 35 mg/day,    about 0.01 mg/day to about 40 mg/day, about 0.01 mg/day to about 45    mg/day, about 0.01 mg/day to about 50 mg/day, about 0.01 mg/day to    about 75 mg/day, or about 0.01 mg/day to about 100 mg/day. In still    other aspects of this embodiment, an effective amount of an ARE    disclosed herein may be in the range of, e.g., about 0.1 mg/day to    about 10 mg/day, about 0.1 mg/day to about 15 mg/day, about 0.1    mg/day to about 20 mg/day, about 0.1 mg/day to about 25 mg/day,    about 0.1 mg/day to about 30 mg/day, about 0.1 mg/day to about 35    mg/day, about 0.1 mg/day to about 40 mg/day, about 0.1 mg/day to    about 45 mg/day, about 0.1 mg/day to about 50 mg/day, about 0.1    mg/day to about 75 mg/day, about 0.1 mg/day to about 100 mg/day,    about 1 mg/day to about 10 mg/day, about 1 mg/day to about 15    mg/day, about 1 mg/day to about 20 mg/day, about 1 mg/day to about    25 mg/day, about 1 mg/day to about 30 mg/day, about 1 mg/day to    about 35 mg/day, about 1 mg/day to about 40 mg/day, about 1 mg/day    to about 45 mg/day, about 1 mg/day to about 50 mg/day, about 1    mg/day to about 75 mg/day, or about 1 mg/day to about 100 mg/day. In    yet other aspects of this embodiment, an effective amount of an ARE    disclosed herein may be in the range of, e.g., about 5 mg/day to    about 10 mg/day, about 5 mg/day to about 15 mg/day, about 5 mg/day    to about 20 mg/day, about 5 mg/day to about 25 mg/day, about 5    mg/day to about 30 mg/day, about 5 mg/day to about 35 mg/day, about    5 mg/day to about 40 mg/day, about 5 mg/day to about 45 mg/day,    about 5 mg/day to about 50 mg/day, about 5 mg/day to about 75    mg/day, or about 5 mg/day to about 100 mg/day.-   130. A method according to any one of embodiments 117-129, wherein    administration is a one-time administration or multiple    administrations.-   131. A method according to any one of embodiments 117-129, wherein    the compound or the pharmaceutical composition is administered    daily, every other day, every third of day, once a week, multiple    times per week, once a month, multiple times per month, once a year    or multiple times per year.-   132. A method according to any one of embodiments 117-129 or 131,    wherein the compound or the pharmaceutical composition is    administered multiple times per day.-   133. A compound as defined in any one of embodiments 1-98 or a    pharmaceutical composition as defined in any one of embodiments    99-114 for use in the treatment of hair loss.-   134. A compound as defined in any one of embodiments 1-98 or a    pharmaceutical composition as defined in any one of embodiments    99-114 for use in the treatment of hair thinning.-   125. A compound as defined in any one of embodiments 1-98 or a    pharmaceutical composition as defined in any one of embodiments    99-114 for use in the treatment of hair color loss.-   136. A compound as defined in any one of embodiments 1-98 or a    pharmaceutical composition as defined in any one of embodiments    99-114 for use in the treatment of a condition associated with a    degenerative hair follicle disorder.-   137. A compound as defined in any one of embodiments 1-98 or a    pharmaceutical composition as defined in any one of embodiments    99-114 for use in improving hair appearance.-   138. A compound as defined in any one of embodiments 1-98 or a    pharmaceutical composition as defined in any one of embodiments    99-114 for use in the treatment of a skin condition.-   139. Use of a compound as defined in any one of embodiments 1-98 or    a pharmaceutical composition as defined in any one of embodiments    99-114 for the treatment of hair loss.-   140. Use of a compound as defined in any one of embodiments 1-98 or    a pharmaceutical composition as defined in any one of embodiments    99-114 for the treatment of hair thinning.-   141. Use of a compound as defined in any one of embodiments 1-98 or    a pharmaceutical composition as defined in any one of embodiments    99-114 for the treatment of hair color loss.-   142. Use of a compound as defined in any one of embodiments 1-98 or    a pharmaceutical composition as defined in any one of embodiments    99-114 for the treatment of a condition associated with a    degenerative hair follicle disorder.-   143. Use of a compound as defined in any one of embodiments 1-98 or    a pharmaceutical composition as defined in any one of embodiments    99-114 for improving hair appearance.-   144. Use of a compound as defined in any one of embodiments 1-98 or    a pharmaceutical composition as defined in any one of embodiments    99-114 for the treatment of a skin condition.-   145. Use of a compound as defined in any one of embodiments 1-98 or    a pharmaceutical composition as defined in any one of embodiments    99-114 in the manufacture of a medicament for the treatment of hair    loss.-   146. Use of a compound as defined in any one of embodiments 1-98 or    a pharmaceutical composition as defined in any one of embodiments    99-114 in the manufacture of a medicament for the treatment of hair    thinning.-   147. Use of a compound as defined in any one of embodiments 1-98 or    a pharmaceutical composition as defined in any one of embodiments    99-114 in the manufacture of a medicament for the treatment of hair    color loss.-   148. Use of a compound as defined in any one of embodiments 1-98 or    a pharmaceutical composition as defined in any one of embodiments    99-114 in the manufacture of a medicament for the treatment of a    condition associated with a degenerative hair follicle disorder.-   149. Use of a compound as defined in any one of embodiments 1-98 or    a pharmaceutical composition as defined in any one of embodiments    99-114 in the manufacture of a medicament for improving hair    appearance.-   150. Use of a compound as defined in any one of embodiments 1-98 or    a pharmaceutical composition as defined in any one of embodiments    99-114 in the manufacture of a medicament for the treatment of a    skin condition.

EXAMPLES

The following non-limiting examples are provided for illustrativepurposes only in order to facilitate a more complete understanding ofrepresentative embodiments now contemplated. These examples should notbe construed to limit any of the embodiments described in the presentspecification, including those pertaining to the compounds,pharmaceutical compositions, or methods and uses disclosed herein.

Example 1 Preparation of Adamantane Precursor

This example illustrates how to prepare Adamantane precursors forsubsequent attachment to a linker molecule disclosed herein.

Scheme 1. Adamantane acetic acid (1.6 g, 8.2 mmol) was dissolved in 20mL dichloromethane and treated with dimethylformamide (2 drops) andoxalyl chloride (2.1 mL, 24.7 mmol) dropwise. The reaction was stirredat ambient temperature for 18 hours, concentrated in vacuo, and placedunder hard vacuum overnight to yield the product as an oil (quant.).

Scheme 2. Adamantane-OH (1.6 g, 8.2 mmol) was dissolved in 20 mLdichloromethane and treated with dimethylformamide (2 drops) and oxalylchloride (2.1 mL, 24.7 mmol) dropwise. The reaction was stirred atambient temperature for 18 hours, concentrated in vacuo, and placedunder hard vacuum overnight to yield the product as an oil (quant.).

Example 2 Preparation of Adamantane-Linker Conjugate

Scheme 3. Adamantane precursor from scheme 1 and linker were suspendedin acetonitrile and treated with 3 equivalents of triethanolaminefollowed by addition of 1 equivalent of acid chloride. The reaction wasstirred for 3 hours, diluted with ethyl acetate and washed with 1 Nhydrochloric acid and brine, dried over sodium sulfate, concentrated,and placed under high vacuum overnight. The resulting Adamantane-linkerconjugate compounds are shown below in scheme 3, where n is from 0 to10.

Using Scheme 3, the following Adamantane-linker conjugate compounds areproduced:

Scheme 4. Adamantane precursor from scheme 1 and linker were suspendedin acetonitrile and treated with 3 equivalents of triethanolaminefollowed by addition of 1 equivalent of acid chloride. The reaction wasstirred for 3 hours, diluted with ethyl acetate and washed with 1 Nhydrochloric acid and brine, dried over sodium sulfate, concentrated,and placed under high vacuum overnight. The resulting Adamantane-linkerconjugate compounds are shown below in scheme 4, where n is from 0 to10.

Using Scheme 4, the following Adamantane-linker conjugate compounds areproduced:

Scheme 5. Adamantane precursor from scheme 2 and linker were suspendedin acetonitrile and treated with 3 equivalents of triethanolaminefollowed by addition of 1 equivalent of acid chloride. The reaction wasstirred for 3 hours, diluted with ethyl acetate and washed with 1 Nhydrochloric acid and brine, dried over sodium sulfate, concentrated,and placed under high vacuum overnight. The resulting Adamantane-linkerconjugate compounds are shown below in scheme 5, where n is from 0 to10.

Using Scheme 5, the following Adamantane-linker conjugate compounds areproduced:

Scheme 6. Adamantane precursor from scheme 2 and linker were suspendedin acetonitrile and treated with 3 equivalents of triethanolaminefollowed by addition of 1 equivalent of acid chloride. The reaction wasstirred for 3 hours, diluted with ethyl acetate and washed with 1 Nhydrochloric acid and brine, dried over sodium sulfate, concentrated,and placed under high vacuum overnight. The resulting Adamantane-linkerconjugate compounds are shown below in scheme 6, where n is from 0 to10.

Using Scheme 6, the following Adamantane-linker conjugate compounds areproduced:

Scheme 7. Adamantane precursor from scheme 2 and linker were suspendedin acetonitrile and treated with 3 equivalents of triethanolaminefollowed by addition of 1 equivalent of acid chloride. The reaction wasstirred for 3 hours, diluted with ethyl acetate and washed with 1 Nhydrochloric acid and brine, dried over sodium sulfate, concentrated,and placed under high vacuum overnight. The resulting Adamantane-linkerconjugate compounds are shown below in scheme 7, where n is from 0 to10.

Using Scheme 7, the following Adamantane-linker conjugate compounds areproduced:

Scheme 8. Adamantane precursor from scheme 2 and linker were suspendedin acetonitrile and treated with 3 equivalents of triethanolaminefollowed by addition of 1 equivalent of acid chloride. The reaction wasstirred for 3 hours, diluted with ethyl acetate and washed with 1 Nhydrochloric acid and brine, dried over sodium sulfate, concentrated,and placed under high vacuum overnight. The resulting Adamantane-linkerconjugate compounds are shown below in scheme 8, where n is from 0 to10.

Using Scheme 8, the following Adamantane-linker conjugate compounds areproduced:

Scheme 9. Adamantane precursor from scheme 2 and linker were suspendedin acetonitrile and treated with 3 equivalents of triethanolaminefollowed by addition of 1 equivalent of acid chloride. The reaction wasstirred for 3 hours, diluted with ethyl acetate and washed with 1 Nhydrochloric acid and brine, dried over sodium sulfate, concentrated,and placed under high vacuum overnight. The resulting Adamantane-linkerconjugate compounds are shown below in scheme 9, where n is from 0 to10.

Using Scheme 9, the following Adamantane-linker conjugate compounds wereproduced:

Scheme 10. Adamantane precursor from scheme 2 and linker were suspendedin acetonitrile and treated with 3 equivalents of triethanolaminefollowed by addition of 1 equivalent of acid chloride. The reaction wasstirred for 3 hours, diluted with ethyl acetate and washed with 1 Nhydrochloric acid and brine, dried over sodium sulfate, concentrated,and placed under high vacuum overnight. The resulting Adamantane-linkerconjugate compounds are shown below in scheme 10, where n is from 0 to10.

Using Scheme 10, the following Adamantane-linker conjugate compoundswere produced:

Reaction schemes similar to schemes 3-10 can be performed except that aHIF-1α can be substituted for the Adamantane precursor from scheme 1 or2.

Example 3 Preparation of HIF-1α-Linker Conjugate

Scheme 11. HIF-1α and linker were suspended in acetonitrile and treatedwith 3 equivalents of triethanolamine followed by addition of 1equivalent of acid chloride. The reaction was stirred for 3 hours,diluted with ethyl acetate and washed with 1 N hydrochloric acid andbrine, dried over sodium sulfate, concentrated, and placed under highvacuum overnight. The resulting HIF-1α-linker conjugate compounds areshown below in scheme 11, where n is from 0 to 10.

Using Scheme 11, the following HIF-1α-linker conjugate compounds wereproduced:

Reaction schemes similar to scheme 11 can be performed except that anyone of the other linkers from schemes 3-8 or 10 can be used.

Example 4 Preparation of Androgen Receptor Antagonist Precursor

This example illustrates how to prepare an AR antagonist disclosedherein for subsequent attachment to a linker molecule disclosed herein.

Scheme 12 show the production of a reactive Spironolactone precursor.Methanol (50 mL) was sparged with nitrogen for 15 minutes, treated withspironolactone (5 g, 12 mmol), chilled over ice and treated dropwisewith 5.4 M sodium methoxide/methanol (5 mL, 27 mmol). The ice bath wasremoved and the reaction was stirred for 40 minutes. The reaction wasplaced in an ice bath and neutralized with acetic acid (1.5 mL) to forma precipitate. More methanol was added and the mixture was sonicated andfiltered. A second crop was filtered. The solid was dried under highvacuum overnight and stored in the freezer.

Scheme 13 show the production of a reactive Ketoconazole precursor.Ketoconazole (800 mg) and 20% sodium hydroxide (2 mL) was heated atreflux in methanol (20 mL) overnight. The solution was cooled to ambienttemperature and water was added. The resulting precipitate was filtered,washed with water, and dried under high vacuum overnight to give 700 mg.

Example 5 Preparation of AR Antagonist-Adamantane-Linker Conjugate

Scheme 14. The reactive Spironolactone precursor (70 mg, 0.18 mg) fromscheme 12 and Adamantane precursor from scheme 1 were dissolved inacetonitrile and treated with N,N-Diisopropylethylamine (78 μL, 0.45mmol). Acid chloride (47 mg, 0.22 mmol) was added and the reaction wasstirred for 8 hours. The reaction was diluted with ethyl acetate andwashed with 1N hydrochloric acid and brine, dried over sodium sulfateand concentrated. Residue was crystallized from ethyl acetate. Thefollowing AR Antagonist-Adamantane-Linker conjugate compound wasproduced.

Scheme 15. The reactive Spironolactone precursor (55 mg, 0.15 mmol) fromscheme 12 and Adamantane-linker conjugate (55 mg, 0.16 mmol) from scheme4 were dissolved in dichloromethane (4 mL) and treated withtriethanolamine (63 μL, 0.45 mmol) andbis(2-oxo-3-oxazolidinyl)phosphinic chloride (41 mg, 0.16 mmol).Reaction was stirred 2 hours. Minimal product had formed.4-dimethylaminopyridine was added and stirring was continued overnight.Reaction was diluted with ethyl acetate and washed with citric acidsaturated sodium bicarbonate and brine. Purified by Si Gelchromatography using ethyl acetate. The following ARAntagonist-Adamantane-Linker conjugate compounds are produced, where nis from 0 to 10.

Using Scheme 15, the following AR Antagonist-Adamantane-Linker conjugatecompounds were produced:

Reaction schemes similar to scheme 15 can be performed except thatinstead of Adamantane precursor from scheme 4, any one of the otherAdamantane precursors from schemes 3 or 5-10 can be used.

Example 6 Preparation of AR Antagonist-Adamantane-Linker Conjugate

Scheme 16. The reactive Ketoconazole precursor (70 mg, 0.18 mg) fromscheme 13 and Adamantane precursor from scheme 1 were dissolved inacetonitrile and treated with N,N-Diisopropylethylamine (78 μL, 0.45mmol). Acid chloride (47 mg, 0.22 mmol) was added and the reaction wasstirred for 8 hours. The reaction was diluted with ethyl acetate andwashed with 1N hydrochloric acid and brine, dried over sodium sulfateand concentrated. Residue was crystallized from ethyl acetate. Thefollowing AR Antagonist-Adamantane-Linker conjugate compound wasproduced.

Scheme 17. The reactive Ketoconazole precursor (55 mg, 0.15 mmol) fromscheme 13 and Adamantane-linker conjugate (55 mg, 0.16 mmol) from scheme4 were dissolved in dichloromethane (4 mL) and treated with 3equivalents of triethanolamine and 1.2 equivalents ofbis(2-oxo-3-oxazolidinyl)phosphinic chloride. Reaction was stirred 2hours. Reaction was diluted with ethyl acetate and washed with sodiumbicarbonate and brine. Purified by Si Gel chromatography using ethylacetate. The following AR Antagonist-Adamantane-Linker conjugatecompounds are produced, where n is from 0 to 10.

Using Scheme 17, the following AR Antagonist-Adamantane-Linker conjugatecompounds were produced:

Reaction schemes similar to scheme 17 can be performed except thatinstead of Adamantane precursor from scheme 4, any one of the otherAdamantane precursors from schemes 3 or 5-10 can be used.

Example 7 Preparation of AR Antagonist-HIF-1α-Linker Conjugate

Scheme 18. The reactive Spironolactone precursor (55 mg, 0.15 mmol) fromscheme 12 and HIF-1α-linker conjugate (55 mg, 0.16 mmol) from scheme 11were dissolved in dichloromethane (4 mL) and treated withtriethanolamine (63 μL, 0.45 mmol) andbis(2-oxo-3-oxazolidinyl)phosphinic chloride (41 mg, 0.16 mmol).Reaction was stirred 2 hours. Minimal product had formed.4-dimethylaminopyridine was added and stirring was continued overnight.Reaction was diluted with ethyl acetate and washed with citric acidsaturated sodium bicarbonate and brine. Purified by Si Gelchromatography using ethyl acetate. The following ARAntagonist-HIF-1α-Linker conjugate compounds are produced, where n isfrom 0 to 10.

Using Scheme 18, the following AR Antagonist-HIF-1α-Linker conjugatecompounds were produced:

Reaction schemes similar to scheme 18 can be performed except thatHIF-1α attached to any one of the other linkers from schemes 3-8 or 10can be used.

Example 8 Preparation of AR Antagonist-HIF-1α-Linker Conjugate

Scheme 19. The reactive Ketoconazole precursor (55 mg, 0.15 mmol) fromscheme 13 and HIF-1α-linker conjugate (55 mg, 0.16 mmol) from scheme 11were dissolved in dichloromethane (4 mL) and treated with 3 equivalentsof triethanolamine and 1.2 equivalents ofbis(2-oxo-3-oxazolidinyl)phosphinic chloride. Reaction was stirred 2hours. Reaction was diluted with ethyl acetate and washed with sodiumbicarbonate and brine. Purified by Si Gel chromatography using ethylacetate. The following AR Antagonist-HIF-1α-Linker conjugate compoundsare produced, where n is from 0 to 10.

Using Scheme 19, the following AR Antagonist-HIF-1α-Linker conjugatecompounds were produced:

Reaction schemes similar to scheme 19 can be performed except thatHIF-1α attached to any one of the other linkers from schemes 3-8 or 10can be used.

Example 9 Preparation of Additional AREs

Using the procedures described in Examples 4-8 the following additionalAREs comprising methoxybenzyl lactam are produced:

Reaction schemes similar to those described in Examples 4-8 can beperformed except that adamantine or HIF-1α attached to any one of theother linkers from schemes 3-9 can be used.

Example 10 Inhibition Assay

This example illustrates how to determine the inhibitory activity of anARE disclosed herein using a cell-based androgen receptortranscriptional reporter assay using an engineered cell line.

For the MDA-kb2 assay, MDA-kb2 mammary gland breast cancer cell line wasmaintained in L-15 media (Gibco) supplemented with 10% FBS, 100 U/mLpenicillin, 100 μg/mL streptomycin, and 0.25 μg/mL amphotericin B at 37°C., without CO₂. For experiments, cells were plated at 1.0×10⁴ cells(50% confluence) per well in 100 μL of medium in 96-well plates. Whencells were attached (after 6 hours), medium was removed and replacedwith dosing medium containing 10% charcoal stripped FBS.

For the Keratinocyte assay, normal Human Adult Primary EpidermalKeratinocyte cell line (ATCC PCS-200-011) was maintained in EPIUFE®Medium, with 60 μM calcium (Thermo MEPISOOCA) supplemented with HumanKeratinocyte Growth Supplement, 100 U/mL penicillin, and 100 μg/mLstreptomycin at 37° C. with 5% C02. For experiments, cells were seededat 70% confluence per well in 100 μL of medium in 96-well plates.Reverse transfection was done on the cells using Lipofectamine 3000(Life Technologies) with plasmids according to manufacturer'sinstructions. Briefly, 0.3 μL transfection reagent per 100 ng DNA wereincubated with P3000 reagent and Opti-Mem prior to addition of cells.After 16 hours, medium was removed and replaced with dosing medium.

A 5α-Androstan-17β-ol-3-one (DHT) stock solution was prepared at 1,000×in ethanol. Each ARE tested was prepared in DMSO. Dosing medium wasprepared at the time of treatment by serial diluting stock solution intomedium. Ethanol concentrations in media never exceeded 0.1%. SPG-001 isSpironolactone; SPG-002 is Ketoconazole; SPG-003 isSpironolactone-Adamantane ARE (Compound 37); SPG-004 isSpironolactone-Adamantane ARE (Compound 39); SPG-005 isKetoconazole-Adamantane ARE (Compound 42); and SPG-006 isKetoconazole-Adamantane ARE (Compound 40). Negative control wellscontained 100 μL medium/well with 1 μL of ethanol/mL of medium and anappropriate amount of DMSO. Each plate also contained 1.0 nM DHT with anARE or without an ARE as a positive control. Cells were incubated 24hours at 37° C. without CO₂.

To assess for cell viability, cells were first visually examined under aphase-contrast microscope to record cell confluence, morphologicalchanges, and presence of drug crystallization as well as to observesigns of cytotoxity such as, e.g., detachment, vacuolization, membranedegradation, or lack of phase brightness. After microscopic inspection,a Trypan Blue exclusion assay was performed to assess cell viability andcell number for each well. Each well was washed with 0.5 mL volume ofPBS. 30 μL of Trypan Blue was added to each well for 5-10 minutes. Totalcell number and total viable cell number will be counted from 1 numberof fields per well, in triplicate.

To assess ARE-mediated inhibition, an AR luciferase assay was performed.After washing cells with 1×PBS, 20 μL lysis buffer (25 mMTris/phosphate, 4 mM EGTA, 1% Triton, 10% glycerol, 2 mM DTT) was addedper well, incubated for 5 minutes with gentle shaking and store at −80°C. On the day of assay, the plates were thawed to ambient temperatureand 80 μL of assay buffer (25 mM glycylglycine, 15 mM MgCl₂. 5 mM ATP,0.1 mg/ml BSA) was added to each well. Plates are then processed on amicroplate reader (POLARstar Omega) by injecting 100 μL of 1 mMD-luciferin per well, followed by chemiluminescence measurement of 3seconds at onset of injection. Luciferase activity was determined,measured, and normalized to Relative Light Units (RLU). AR reporter geneactivity reduction values were calculated as follows: AR reporter geneactivity=1−(average signal(treatment group)/average signal(treatmentgroup without drug).

To assess levels of AR, an ELISA was performed.

The results of two independent MDA-kb2 assays are shown in Table 1. Adose-dependent inhibition of AR reporter gene activity was observed forall compounds tested. In addition, the addition of an AR eliminationpromoter or elimination enhancer element significantly increased thedegree of inhibition observed. For example, Spironolactone demonstrated41% reduction in AR reporter gene activity at 10 μM, while SPG-003exhibited 90% reduction in AR reporter gene activity at 10 μM (Table 1).Similarly, Ketoconazole demonstrated 43% reduction in AR reporter geneactivity at 10 μM, while SPG-005 exhibited 80% reduction in AR reportergene activity at 10 μM (Table 1). A dose-dependent reduction in ARprotein levels were also observed for all compounds tested. In addition,the addition of an AR elimination promoter or elimination enhancerelement significantly increased the degree of inhibition observed. Forexample, Spironolactone demonstrated 35% reduction in AR protein levelat 10 μM, while SPG-003 exhibited 71% reduction in AR protein level at10 μM (Table 1). Similarly, Ketoconazole demonstrated 10% reduction inAR protein level at 10 μM, while SPG-005 exhibited 54% reduction in ARprotein level at 10 μM (Table 1).

TABLE 1 MDA-KB2 AR Reporter Gene Assay Gene Activity Treatment CellViability Reduction AR Reduction Negative Control 99% 0% 0% PositiveControl 99% 80% * 43% * 0.1 μM SPG-001 99% 12% * — 1.0 μM SPG-001 98%28% * — 3.0 μM SPG-001 98% 39% * 31% *  10 μM SPG-001 98% 41% * 35% *0.1 μM SPG-002 97%  4% * — 1.0 μM SPG-002 98%  7% * — 3.0 μM SPG-002 98%16% *  4% *  10 μM SPG-002 98% 43% * 10% * 0.1 μM SPG-003 98%  8% * —1.0 μM SPG-003 99% 20% * — 3.0 μM SPG-003 98% 40% * 25% *  10 μM SPG-00398% 90% * 71% * 0.1 μM SPG-004 97% 11% * — 1.0 μM SPG-004 98% 22% * —3.0 μM SPG-004 99% 36% * 29% *  10 μM SPG-004 98% 42% * 50% * 0.1 μMSPG-005 98%  9% * — 1.0 μM SPG-005 98% 14% * — 3.0 μM SPG-005 98% 18% * 8% *  10 μM SPG-005 98% 80% * 54% * 0.1 μM SPG-006 — — — 1.0 μM SPG-006— — — 3.0 μM SPG-006 — — —  10 μM SPG-006 — — — * p-value < 0.05(T-test) compared to respective control and has inhibitory effect.

The results of a Keratinocyte assays are shown in Table 2. Adose-dependent inhibition of AR reporter gene activity was observed forall compounds tested. In addition, the addition of an AR eliminationpromoter or elimination enhancer element significantly increased thedegree of inhibition observed. For example, Spironolactone demonstrated59% reduction in AR reporter gene activity at 10 μM, while SPG-003exhibited 93% reduction in AR reporter gene activity at 10 μM (Table 2).Similarly, Ketoconazole demonstrated 56% reduction in AR reporter geneactivity at 10 μM, while SPG-005 exhibited 90% reduction in AR reportergene activity at 10 μM (Table 2). A dose-dependent reduction in ARprotein levels were also observed for all compounds tested. In addition,the addition of an AR elimination promoter or elimination enhancerelement significantly increased the degree of inhibition observed. Forexample, Spironolactone demonstrated 51% reduction in AR protein levelat 10 μM, while SPG-003 exhibited 65% reduction in AR protein level at10 μM (Table 2). Similarly, Ketoconazole demonstrated 20% reduction inAR protein level at 10 μM, while SPG-005 exhibited 65% reduction in ARprotein level at 10 μM (Table 2).

TABLE 2 Keratinocyte AR Reporter Gene Assay Gene Activity Treatment CellViability Reduction AR Reduction Negative Control 94% 0% 0% PositiveControl 95% 90% * 52% * 0.1 μM SPG-001 92% 21% * 12% * 1.0 μM SPG-00194% 37% * 30% * 3.0 μM SPG-001 92% 54% * 42% *  10 μM SPG-001 95% 59% *51% * 0.1 μM SPG-002 95% 13% * 2% 1.0 μM SPG-002 93% 18% * 10% * 3.0 μMSPG-002 94% 30% * 11% *  10 μM SPG-002 95% 56% * 20% * 0.1 μM SPG-00393% 21% *  6% * 1.0 μM SPG-003 93% 31% * 19% * 3.0 μM SPG-003 94% 50% *26% *  10 μM SPG-003 93% 93% * 65% * 0.1 μM SPG-004 — — — 1.0 μM SPG-004— — — 3.0 μM SPG-004 — — —  10 μM SPG-004 — — — 0.1 μM SPG-005 94% 21% *12% * 1.0 μM SPG-005 92% 29% * 19% * 3.0 μM SPG-005 93% 31% * 23% *  10μM SPG-005 94% 90% * 65% * 0.1 μM SPG-006 93%  8% * 1% 1.0 μM SPG-00694% 19% *  5% * 3.0 μM SPG-006 94% 28% * 20% *  10 μM SPG-006 94% 48% *37% * * p-value < 0.05 (T-test) compared to respective control and hasinhibitory effect.

Example 11 Inhibition Assay

This example illustrates how to determine the inhibitory activity of anARE disclosed herein using a cell-based androgen receptortranscriptional reporter assay using primary human keratinoctyes.

For the Keratinocyte assay, normal Human Adult Primary EpidermalKeratinocyte cell line (ATCC PCS-200-011) was maintained in EPIUFE®Medium, with 60 μM calcium (Thermo MEPISOOCA) supplemented with HumanKeratinocyte Growth Supplement, 100 U/mL penicillin, and 100 μg/mLstreptomycin at 37° C. with 5% C02. For experiments, cells were seededat 70% confluence per well in 100 μL of medium in 96-well plates.Reverse transfection was done on the cells using Lipofectamine 3000(Life Technologies) with plasmids according to manufacturer'sinstructions. Briefly, 0.3 μL transfection reagent per 100 ng DNA wereincubated with P3000 reagent and Opti-Mem prior to addition of cells.After 16 hours, medium was removed and replaced with dosing medium.

To assess ARE-mediated inhibition, an AR luciferase assay was performedas described in Example 10. To assess levels of AR, an ELISA wasperformed as described in Example 10.

A Nicosamide stock solution was prepared at 1,000× in ethanol. Each AREtested was prepared in DMSO. Dosing medium was prepared at the time oftreatment by serial diluting stock solution into medium. Ethanolconcentrations in media never exceeded 0.1%. SPG-001 is Spironolactone;SPG-002 is Ketoconazole; SPG-003 is Spironolactone-Adamantane ARE(Compound 37); and SPG-005 is Ketoconazole-Adamantane ARE (Compound 42).Negative control wells contained 100 μL medium/well with 1 μL ofethanol/mL of medium and an appropriate amount of DMSO. Each ARE wasapplied to keratinocytes in concentrations up to 50 μM. Each plate alsocontained 1.0 nM Nicosamide with an ARE or without an ARE as a positivecontrol. Cells were incubated 72 hours at 37° C. without CO₂.

The results are shown in Table 3. IC₅₀ values were calculated asfollows: SPG-001: 50 μM; SPG-002: 11 μM; SPG-003: about 50 μM; SPG-005:2 μM; and Niclosamide: <0.2 μM. The results showed that both SPG-001 andSPG-003 had essentially the same cytotoxic effects with equivalent IC₅₀values when 50 μM of each was applied to keratinocytes. Niclosamide, adrug previously shown to be cytotoxic to these cells had an IC₅₀ ofbelow 0.2 μM. These results indicate that SPG-003 had comparablecytotoxicity in skin cells to its parent, the AR antagonistSpironolactone (Table 3).

TABLE 3 Cell Viability Assay Concentration (μM) SPG-001 SPG-002 SPG-003SPG-005 Niclosamide 50  58.33 ± 2.39  7.29 ± 12.16 38.67 ± 2.25  0.09 ±6.41  0.20 ± 6.09 16.67  82.73 ± 1.34 41.59 ± 1.76 55.11 ± 0.16  0.11 ±1.77 15.93 ± 7.45 5.56  99.27 ± 1.50 71.22 ± 0.88 66.12 ± 3.09  1.98 ±8.39 25.07 ± 3.81 1.85 108.09 ± 1.79 90.96 ± 2.34 73.46 ± 1.11 62.57 ±2.06 30.65 ± 5.98 0.62 113.05 ± 1.09 93.61 ± 3.38 92.16 ± 1.30 77.01 ±0.64 34.13 ± 2.99 0.21 116.28 ± 2.79 110.17 ± 0.78  115.90 ± 0.49  93.72± 1.69 45.57 ± 4.55 0   100 ± 0.79   100 ± 0.79   100 ± 0.79   100 ±0.79   100 ± 0.79

Example 12 Inhibition Assay

This example illustrates how to determine the inhibitory activity of anARE disclosed herein using a cell-based androgen receptortranscriptional reporter assay using primary human keratinoctyes.

To assess ARE-mediated inhibition, an AR luciferase assay was performedas described in Example 10 to examine the effects of SPG-001(Spironolactone), SPG-002 (Ketoconazole), SPG-003 (aSpironolactone-Adamantane ARE, Compound 37), SPG-007 (aKetoconazole-HIF-1α ARE, Compound 47), SPG-008 (a Ketoconazole-HIF-1αARE, Compound 49), and SPG-009 (a Spironolactone-HIF-1α ARE, Compound43) after continuous exposure for 24 and 72 hours. To assess levels ofAR, an ELISA was performed as described in Example 10. Results wereanalyzed for IC₅₀ and IC₉₀ values in GraphPad Prism using afour-parameter logistic curve equation. Bottom constraints were set to 1(level of uninduced control). All reported values had an R-square valuegreater than 0.96.

At both time points in this experiment, SPG-003 was superior to SPG-001(Table 4). For example, the maximum observed inhibition of reporter geneactivity was 65% for SPG-001 and 91% for SPG-003 after 24 hours oftreatment. The IC₅₀ for SPG-003 for the 24-hr treatment was 3.7 μM andthe IC₉₀ was 7 μM. Neither parameter could be calculated for SPG-001 inthis experiment. SPG-003 was the best performing compound of the grouptested in this study.

As was seen in the 24-hour treatment, SPG-003 was superior to SPG-001 inboth IC₅₀ and IC₉₀ as well as maximum observed inhibition of reportergene activity after the 72-hour treatment. Interestingly, the calculatedIC₅₀ of SPG-003 was reduced from 3.7 μM to 2.5 μM (Table 4). Thecalculated IC₉₀ of SPG-003 was also reduced from 7 μM to 5.7 μM (Table4). This suggests that extended treatment with SPG-003 results in betterinhibition of the target AR reporter gene. A dose-dependent inhibitionof AR reporter gene activity was observed for SPG-003. SPG-003 hadincreased potency and inhibition of AR reporter gene activity withextended treatment while cell cytotoxicity was minimal in humankeratinocytes.

TABLE 4 Keratinocyte AR Reporter Gene Assay 24-hr Treatment 72-hrTreatment Maximum Maximum Compound IC₅₀ (M) IC₉₀ (M) Inhibition IC₅₀ (M)IC₉₀ (M) Inhibition SPG-001 No S-curve No S-curve 65% 4.51 × 10⁻⁶ 1.66 ×10⁻⁶ 85% SPG-002 5.45 × 10⁻⁶ 9.67 × 10⁻⁵ 59% 2.39 × 10⁻⁶ 1.84 × 10⁻⁵ 83%SPG-003 3.68 × 10⁻⁶ 6.96 × 10⁻⁶ 91% 2.57 × 10⁻⁶ 5.68 × 10⁻⁶ 93% SPG-0074.58 × 10⁻⁶ 7.38 × 10⁻⁵ 67% 1.50 × 10⁻⁶ 2.22 × 10⁻⁵ 80% SPG-008 3.31 ×10⁻⁶ 8.40 × 10⁻⁶ 94% 2.38 × 10⁻⁶ 7.86 × 10⁻⁶ 94% SPG-009 4.58 × 10⁻⁶1.12 × 10⁻⁵ 90% 3.05 × 10⁻⁶ 8.17 × 10⁻⁶ 92%

The sustained effects of SPG-001 versus SPG-003 was also examined inhuman keratinocytes transfected with an AR luciferase reporter gene.Cells were transfected with the reporter gene and then treated with 7 μMSPG-001 or 7 μM SPG-003 for 24 hours. After 24 hours, the cells werewashed and media was replaced with new media that did not contain any ARantagonist. Reporter gene activity was measured following two days orthree days of additional cell culture in the absence of AR antagonists.AR reporter gene activity reduction was calculated as follows:1−(average signal(treatment group)/(average signal(treatment group,without drug, same washout period).

The results of that experiment showed that SPG-003 had sustainedinhibition of reporter gene activity over three days that wassignificantly better than what was observed with cells treated withSPG-001. For example, as seen in Table 5, three days after the removalof SPG-003, reporter gene activity was suppressed by 48% in SPG-003treated cells. However, cells treated with SPG-001 at that sameconcentration only showed 24% inhibition of the reporter gene. Thesedata again highlight the superiority of SPG-003 as an AR antagonist incomparison to its parent SPG-001 (spironolactone). Cell viability wasbetween 90% and 100% for both compounds over the duration of this study.

TABLE 5 Keratinocyte AR Reporter Gene Assay Washout Period Niclosamide(0.5 μM) SPG-001 (7.0 μM) SPG-003 (7.0 μM) 0 days 90 ± 0.2%* 67 ± 1.1%*89 ± 1.0%* 2 days 70 ± 0.9%* 40 ± 2.5%* 64 ± 0.3%* 3 days 58 ± 2.6%* 24± 2.3%* 48 ± 2.4%* *p-value < 0.05 (T-test) compared to respectivecontrol and has inhibitory effect.

Example 13 Inhibition Assay

This example illustrates how to determine the inhibitory activity of anARE disclosed herein using a cell-based androgen receptortranscriptional reporter assay using primary human keratinoctyes.

To determine efficacy of a compound, a MDA-kb2 assay was performed asdescribed in Example 10. The cells were treated with compounds for 24hours prior to measurements of reporter gene activity. The IC₅₀ and IC₉₀of SPG-001 and SPG-003 was determined in MDA-kb2 cells treated with 0.1nM DHT for 24 hours. AR luciferase assay results were analyzed usingGraphPad Prism using a four-parameter logistic curve equation. Bottomconstraints were set at 1 (level of uninduced control.)

Even though hormone levels were reduced to better model the parametersof female human skin, reporter gene activity was still quite significantwith a 12-fold induction relative to control cells not exposed to DHT.In this experiment, SPG-001 had no apparent ability to inhibit reportergene activity. Cyproterone acetate, an approved AR antagonist actuallydemonstrated AR agonistic activity at concentrations above 3.3 μM withlimited antagonistic activity at concentrations below 1 μM. SPG-003showed a maximum inhibition of reporter gene activity of 95%, an IC₅₀ of789 nM, an IC₉₀ of 2.71 μM. MDA-kb2 breast cancer cell viability startedto decline from 80% to 50% upon treatment with 6 μM to 10 μM of SPG-003though this phenomenon was not previously seen in similar experimentswith this cell line and should be investigated more carefully. Theseexperiments demonstrated a dose-dependent inhibition of AR reporter geneactivity for SPG-003. This dose-dependent inhibition was not observedfor SPG-001 or Cyproterone acetate under conditions of reduced (10-foldrelativity previous experiments) DHT levels.

TABLE 6 MDA-kb2 Assay Compound IC₅₀ (M) IC₉₀ (M) Maximum InhibitionSPG-001 — —  0% SPG-003 7.89 x 10⁻⁷ 2.71 x 10⁻⁶ 95% Cyproterone acetate— — 24% * p-value < 0.05 (T-test) compared to respective control and hasinhibitory effect.

Example 14 Formulation Studies

A study was conducted to develop and experimental formulation for thetopical delivery of SPG-003 to human and mouse skin. The results ofthose studies identified experimental formulations which were thenapplied to both human and mouse skin using standard FDC chambers. Aformulation consisting of IPM/Ethanol/Transcutol/49.8/30/20 w/w/w wasidentified from these formulation studies as optimal. These studiesdemonstrated significant permeation into the dermis and epidermis ofSPG-003 and suggested that these formulations could be used toeffectively inhibit the AR in vivo when applied topically.

Solubility screening tests were performed in 8 solvent systems: (1)Transcutol:Ethanol:Isopropyl myristate (IPM) 2:3:5 (v:v); (2)Transcutol:Ethanol 3:7 (v:v); (3) Ethanol:Propylene Glycol 1:1 (v:v);(4) Ethanol:H2O 7:3 (v:v); (5) IPM; (6) Ethanol:Tween 80:Cetyl Alcohol90:5:5 (w:w); (7) CCT: Tween 80:Cetyl Alcohol 90:5:5 (w:w); and (8)CCT:Isopropanol 1:1 (v:v). These solvent systems were selected from FDAInactive Ingredients Database (IIG). One objective was to identifysolvent systems for solution formulation at targeted API concentrationof 1% by weight. Another objective was to identify solvents that arepotentially good penetration enhancers and yet clinically viable. Sincecetyl alcohol is solid, the solvent systems with them were prepared inweight ratios.

For solvent systems (3), (4), (5) and (7), SPG-003 was not soluble afterextensive sonication. For solvent (1), (2), (6) and (8), SPG-003 hadgood solubility in those solvent systems. Transcutol:Ethanol:IPM 2:3:5(v:v) was picked as solution formulation since it has a good penetrationenhancer (transcutol) and a lipid IPM (clinically viable).

To examine the penetration ability of SPG-003 formulation, two differentassays were conducted. The SPG-003 formulation was prepared by addingSPG-003 (final concentration 1.0% by weight) to a mixture comprising 30%denatured alcohol. 49% IPM, 20% Transcutol and sonicating this mixtureuntil the compound was dissolved.

Human cadaver skin tissue was purchased from a tissue bank in the U.S.Two lots of the dermatomed skin tissue were used. Donor demographics:tissue 08033 (average thickness: 397 μm): sex=male, age=58,race=Caucasian, and anatomical site=abdomen; tissue 08696 (averagethickness: 1,040 μm): sex=male, age=50, race=Caucasian, and anatomicalsite=abdomen. The thickness was measured using a digital snap gage.Duplicate for each donor (N=2). The tissue was received in dry icepackaging. It was stored at −20° C. until use.

After passing initial visual inspection, barrier integrity of the skintissue was evaluated using transepidermal electrical resistancemeasurement (TEER measurement). Measurement was conducted using a LCRmeter at a frequency of 100 Hz at room temperature. The measurementmedium was 0.9% NaCl solution, using a pair of stainless steelelectrodes. Prior to the skin absorption and penetration study,electrical resistance value for each lot of human skin tissue wasevaluated. Due to potential lot-to-lot variation in donor age, sex,race, and anatomical site, objective of the measurement was to establishthreshold value for intact cadaver tissue for each lot to be used in thepresent skin absorption and penetration study. Six (6) tissue samplesfrom selected spots from each lot were taken. Transepidermal electricalresistance value (TEER measurement, Z value) was measured. All reportedTEER values are net values after subtraction of the measurement mediumblank (about 1.3 KOhms). It was determined that the threshold TEER valuewas 6.0 KOhms for donor 08033 and 10 KOhms for donor 08696. For thosetissues with visible defects, the TER value was found in the range of0.1 KOhms to 0.5 KOhms.

The formulation screening study was carried out in a High-ThroughputScreening (HTS) station. The skin tissue samples (after washed with1×PBS, pH 7.4) were mounted on diffusion cells in HTS station. A totalof 4 cells were used in the study. Each cell in the station has adiffusion area of 0.503 cm² (8 mm in diameter). Each individual cell isstatic Franz-Cell type. The receptor chamber was filled with 3.0 mL of4% BSA in water, supplemented with 0.01% gentamicin sulfate, which wasvigorously and continuously mixed. The temperature was set at 32±0.1° C.The tissue samples in the HTS cells were equilibrated at 32±0.1° C. for1 hour before dosing. The applied SPG-003 formulation dose for eachsample was 5.0 μL and each sample was run in two replicates.

The data collection time point was 8 hours. At end of the time interval,the skin tissues were removed from the cells. The tissue surface wascarefully wiped with Q-tip wetted with distilled water, followed bywiping with dry Q-tip one time; then, wiped with Q-tip wetted withdistilled water, followed by wiping with dry Q-tip one more time. Then,two cycles of tape-stripping were performed to remove residualformulation left on the skin surface (un-absorbed/un-penetrated). Then,the standard tape-stripping method was used to remove the SC layer.Scotch tape was used in tape-stripping process. The tape-stripping cyclewas repeated for a total of 15 times. It has been established in ourlaboratory that 15-stripping-cycle is sufficient to completely removethe SC layer from human cadaver skin. The collected tape strips werediscarded. After removal of the SC layer, epidermis and dermis layerwere cut into pieces and extracted with 7.0 ml of DMSO/ACN=1:1 v/v forovernight at room temperature using an orbit shaker. The extracts werecollected and ready for analysis. The receptor fluid was collected andprepared for analysis. A liquid chromatography-tandem mass spectrometry(LC-MS/MS) method was developed for the quantitation of SPG-003 in BSAand human skin soaked in DMSO/ACN=1:1 v/v matrix samples. Theconcentration range of the SPG-003 calibration was 1 ng/mL to 120 ng/mLfor BSA matrix and 10 ng/mL to 1000 ng/mL for human ear skin soaked inDMSO/ACN=1:1 v/v matrix samples.

TABLE 7 Human Skin Penetration Assays Donor 08033 Donor 08696 Assay Run1 Run 2 Run 1 Run 2 Receptor - 8 hr 1.4 ng 0.9 ng 1.2 ng 1.0 ngEpidermis/ 931.0 ng 471.8 ng 3311.0 ng 1897.0 ng Dermis - 8 hrEpidermis/ 89.1 μM 45.1 μM 117.1 μM 67.1 μM Dermis - 8 hr

Compound SPG-003 shows limited amount of skin penetration, but goodamount of skin retention in epidermis and dermis after 8 hours ofexposure.

Based on the results above, a similar skin penetration study wasperformed using hamster skin model. Both SPG-003 and Spironolactone wereformulated with Transcutol:Ethanol:IPM 2:3:5 (v:v) as described above.The applied formulation dose for each sample was 10.0 μL and each samplewas run in four replicates. The samples were evaluated at the 8-hourtime point for compound absorption in epidermal and dermal layers andpenetration into receptor medium.

TABLE 8 Hamster Skin Penetration Assays SPG-003 Formulation Assay Run 1Run 2 Run 3 Run 4 Receptor - 8hr 2.46 5.28 3.69 5.70 Epidermis/Dermis -8 hr 12840 9120 11960 4200 Receptor - 8 hr 4230 2997 2781 3690Epidermis/Dermis - 8 hr 6240 6760 5600 13360

Compound SPG-003 has limited amount of skin penetration, but it has goodamount of skin absorption. In other words, it mainly retained inepidermis/dermis layer. Compound Spironolactone has good amount of skinpenetration and absorption.

Example 15 In Vivo Androgenetic Alopecia Studies

These experiments tested stability of the SPG-003 formulation in asolution was well as mouse skin homogenate.

To test formulation stability in solution, about 100 mg of the SPG-003formulation was weighted in a 4 mL vial and 3 mL of ethanol was added tofully dissolve the formulation. Then 300 μL of ethanol solution wasadded into 700 μL of acetonitrile/H₂O (70/30 v/v) to make 1 mL of finalsolution and mixed well for HPLC analysis. The solution formulations ofSPG-003 were stored at room temperature (20° C.) and 4° C. up to 21 daysand the potency was tested at TO and 21 days.

TABLE 9 SPG-003 Formulation Stability in Solution Incubation ConditionsRun1 Run 2 Run 3 Mean Before Incubation 0.19% 0.19% 0.19% 0.19% 4° C.Incubation - 21 days 0.19% 0.18% 0.19% 0.19% 20° C. Incubation - 21 days0.19% 0.19% 0.19% 0.19%

To test formulation stability in a tissue homogenate, the SPG-003formulation was incubated in mouse skin homogenate at 32° C. for 24hours. After this incubation period, 10 times volume of acetonitrile wasadded into the homogenate samples to quench the reaction and precipitatethe protein. Then the samples were centrifuged and the clear supernatantwas analyzed by HPLC.

TABLE 10 SPG-003 Formulation Stability in Solution Incubation ConditionsRun 1 Run 2 Run 3 Mean Before 95.29 μg/mL 96.85 μg/mL 98.63 μg/mL 96.90μg/mL Incubation After 83.74 μg/mL 99.10 μg/mL 90.25 μg/mL 91.03 μg/mLIncubation - 21 days

These experiments indicate that the SPG-003 formulation shows the goodstability in solution for at least up to 21 days storage both at roomtemperature and 4° C. In addition, this formulation is stable in mouseskin homogenate up to 24 hours of incubation at 32° C.

Example 16 In Vivo Androgenetic Alopecia Studies

A mouse model of androgenetic alopecia will be utilized to demonstratethe activity of an ARE disclosed herein. The backs of 7 week old maleC57BL/6 mice will be shaved and depilated at the start of the study and100 uL of 1% testosterone will be applied to the back of each mouse on adaily basis to suppress hair regrowth. 10 uL of each ARE will also beapplied topically on a daily basis to mice in the presence of 1%testosterone. Depilation will synchronize all the hair follicles intothe growth or anagen phase of the hair cycle while the exogenoustestosterone will act to suppress hair growth. In the absence oftestosterone, complete hair regrowth typically occurs within 14 days.The presence of testosterone delays hair regrowth for about 7 days. Upthe addition of an ARE, the delay in regrowth will be reversed, therebydemonstrating the ability of the compound to block the hair growthinhibitory effects of androgens in vivo. Each experimental treatmentgroup of mice will consist of 8-10 animals.

Example 17 In Vivo Sebum Reduction Model

The Syrian hamster ear model will be used to demonstrate the ability ofan ARE disclosed herein to suppress sebum production when topicallyapplied. Each ARE will be applied for two weeks. At the completion ofthe study, animals will be sacrificed, the wax esters extracted andanalyzed for lipid content as that has been shown to correlate very wellwith sebum production. In addition, sebaceous gland size will beevaluated histologically as an independent measurement of sebumproduction. It has been shown that oral AR antagonists such asspironolactone and cyproterone acetate are effective at reducing bothsebum production and acne severity in females.

In closing, it is to be understood that although aspects of the presentspecification are highlighted by referring to specific embodiments, oneskilled in the art will readily appreciate that these disclosedembodiments are only illustrative of the principles of the subjectmatter disclosed herein. Therefore, it should be understood that thedisclosed subject matter is in no way limited to a particular compound,composition, article, apparatus, methodology, protocol, and/or reagent,etc., described herein, unless expressly stated as such. In addition,those of ordinary skill in the art will recognize that certain changes,modifications, permutations, alterations, additions, subtractions andsub-combinations thereof can be made in accordance with the teachingsherein without departing from the spirit of the present specification.It is therefore intended that the following appended claims and claimshereafter introduced are interpreted to include all such changes,modifications, permutations, alterations, additions, subtractions andsub-combinations as are within their true spirit and scope.

Certain embodiments of the present invention are described herein,including the best mode known to the inventors for carrying out theinvention. Of course, variations on these described embodiments willbecome apparent to those of ordinary skill in the art upon reading theforegoing description. The inventor expects skilled artisans to employsuch variations as appropriate, and the inventors intend for the presentinvention to be practiced otherwise than specifically described herein.Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above-describedembodiments in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

Groupings of alternative embodiments, elements, or steps of the presentinvention are not to be construed as limitations. Each group member maybe referred to and claimed individually or in any combination with othergroup members disclosed herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Unless otherwise indicated, all numbers expressing a characteristic,item, quantity, parameter, property, term, and so forth used in thepresent specification and claims are to be understood as being modifiedin all instances by the term “about.” As used herein, the term “about”means that the characteristic, item, quantity, parameter, property, orterm so qualified encompasses a range of plus or minus ten percent aboveand below the value of the stated characteristic, item, quantity,parameter, property, or term. Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the specification andattached claims are approximations that may vary. For instance, as massspectrometry instruments can vary slightly in determining the mass of agiven analyte, the term “about” in the context of the mass of an ion orthe mass/charge ratio of an ion refers to +/−0.50 atomic mass unit. Atthe very least, and not as an attempt to limit the application of thedoctrine of equivalents to the scope of the claims, each numericalindication should at least be construed in light of the number ofreported significant digits and by applying ordinary roundingtechniques.

Use of the terms “may” or “can” in reference to an embodiment or aspectof an embodiment also carries with it the alternative meaning of “maynot” or “cannot.” As such, if the present specification discloses thatan embodiment or an aspect of an embodiment may be or can be included aspart of the inventive subject matter, then the negative limitation orexclusionary proviso is also explicitly meant, meaning that anembodiment or an aspect of an embodiment may not be or cannot beincluded as part of the inventive subject matter. In a similar manner,use of the term “optionally” in reference to an embodiment or aspect ofan embodiment means that such embodiment or aspect of the embodiment maybe included as part of the inventive subject matter or may not beincluded as part of the inventive subject matter. Whether such anegative limitation or exclusionary proviso applies will be based onwhether the negative limitation or exclusionary proviso is recited inthe claimed subject matter.

Notwithstanding that the numerical ranges and values setting forth thebroad scope of the invention are approximations, the numerical rangesand values set forth in the specific examples are reported as preciselyas possible. Any numerical range or value, however, inherently containscertain errors necessarily resulting from the standard deviation foundin their respective testing measurements. Recitation of numerical rangesof values herein is merely intended to serve as a shorthand method ofreferring individually to each separate numerical value falling withinthe range. Unless otherwise indicated herein, each individual value of anumerical range is incorporated into the present specification as if itwere individually recited herein.

The terms “a,” “an,” “the” and similar references used in the context ofdescribing the present invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. Further, ordinal indicators—such as “first,” “second,” “third,”etc.—for identified elements are used to distinguish between theelements, and do not indicate or imply a required or limited number ofsuch elements, and do not indicate a particular position or order ofsuch elements unless otherwise specifically stated. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein is intended merely to better illuminate the presentinvention and does not pose a limitation on the scope of the inventionotherwise claimed. No language in the present specification should beconstrued as indicating any non-claimed element essential to thepractice of the invention.

When used in the claims, whether as filed or added per amendment, theopen-ended transitional term “comprising” (and equivalent open-endedtransitional phrases thereof like including, containing and having)encompasses all the expressly recited elements, limitations, stepsand/or features alone or in combination with unrecited subject matter;the named elements, limitations and/or features are essential, but otherunnamed elements, limitations and/or features may be added and stillform a construct within the scope of the claim. Specific embodimentsdisclosed herein may be further limited in the claims using theclosed-ended transitional phrases “consisting of” or “consistingessentially of” in lieu of or as an amended for “comprising.” When usedin the claims, whether as filed or added per amendment, the closed-endedtransitional phrase “consisting of” excludes any element, limitation,step, or feature not expressly recited in the claims. The closed-endedtransitional phrase “consisting essentially of” limits the scope of aclaim to the expressly recited elements, limitations, steps and/orfeatures and any other elements, limitations, steps and/or features thatdo not materially affect the basic and novel characteristic(s) of theclaimed subject matter. Thus, the meaning of the open-ended transitionalphrase “comprising” is being defined as encompassing all thespecifically recited elements, limitations, steps and/or features aswell as any optional, additional unspecified ones. The meaning of theclosed-ended transitional phrase “consisting of” is being defined asonly including those elements, limitations, steps and/or featuresspecifically recited in the claim whereas the meaning of theclosed-ended transitional phrase “consisting essentially of” is beingdefined as only including those elements, limitations, steps and/orfeatures specifically recited in the claim and those elements,limitations, steps and/or features that do not materially affect thebasic and novel characteristic(s) of the claimed subject matter.Therefore, the open-ended transitional phrase “comprising” (andequivalent open-ended transitional phrases thereof) includes within itsmeaning, as a limiting case, claimed subject matter specified by theclosed-ended transitional phrases “consisting of” or “consistingessentially of.” As such embodiments described herein or so claimed withthe phrase “comprising” are expressly or inherently unambiguouslydescribed, enabled and supported herein for the phrases “consistingessentially of” and “consisting of.”

All patents, patent publications, and other publications referenced andidentified in the present specification are individually and expresslyincorporated herein by reference in their entirety for the purpose ofdescribing and disclosing, for example, the compositions andmethodologies described in such publications that might be used inconnection with the present invention. These publications are providedsolely for their disclosure prior to the filing date of the presentapplication. Nothing in this regard should be construed as an admissionthat the inventors are not entitled to antedate such disclosure byvirtue of prior invention or for any other reason. All statements as tothe date or representation as to the contents of these documents isbased on the information available to the applicants and does notconstitute any admission as to the correctness of the dates or contentsof these documents.

Lastly, the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to limit the scope ofthe present invention, which is defined solely by the claims.Accordingly, the present invention is not limited to that precisely asshown and described.

The invention claimed is:
 1. A compound having the structure of formulaI,

wherein ARA is an AR antagonist that is apalutamide, bicalutamide,canrenone, chlormadinone acetate, cimetidine, cyproterone acetate,drospirenone, enzalutamide, flutamide, ketoconazole, megestrol acetate,nilutamide, RU58841, spironolactone, topilutamide (fluridil),


2. The compound according to claim 1, wherein the compound is


3. The compound according to claim 1, wherein the compound is


4. A pharmaceutical composition comprising a compound according toclaim
 1. 5. The pharmaceutical composition according to claim 4, furthercomprising one or more pharmaceutically acceptable carriers and/or oneor more pharmaceutically acceptable components.
 6. The pharmaceuticalcomposition according to claim 4, further comprising 20% to 40%denatured alcohol, 40% to 60% isopropyl myristate, and 10% to 30%diethylene glycol monoethyl ether.
 7. The pharmaceutical compositionaccording to claim 4, further comprising 25% to 35% denatured alcohol,45% to 55% isopropyl myristate, and 15% to 25% diethylene glycolmonoethyl ether.
 8. A pharmaceutical composition comprising: 0.1% to 10%of a compound having the structure of

wherein ARA is an AR antagonist that is apalutamide, bicalutamide,canrenone, chlormadinone acetate, cimetidine, cyproterone acetate,drospirenone, enzalutamide, flutamide, ketoconazole, megestrol acetate,nilutamide, RU58841, spironolactone, topilutamide (fluridil),

20% to 40% denatured alcohol, 40% to 60% isopropyl myristate, and 10% to30% diethylene glycol monoethyl ether.
 9. The pharmaceutical compositionaccording to claim 8, wherein the compound is


10. A pharmaceutical composition comprising: 0.5% to 5% of a compoundhaving the structure of

wherein ARA is an AR antagonist that is apalutamide, bicalutamide,canrenone, chlormadinone acetate, cimetidine, cyproterone acetate,drospirenone, enzalutamide, flutamide, ketoconazole, megestrol acetate,nilutamide, RU58841, spironolactone, topilutamide (fluridil),

25% to 35% denatured alcohol, 45% to 55% isopropyl myristate, and 15% to25% diethylene glycol monoethyl ether.
 11. The pharmaceuticalcomposition according to claim 10, wherein the compound is